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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294
Volume 19, 32 Issues, 2019
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Selected Heterocyclic Compounds as Antioxidants. Synthesis and Biological Evaluation, 2014 :14(22); 2462 - 2477
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It has been a wonderful experience publishing our research paper with Bentham Science Publishers, who is very prompt and professional in providing excellent services. Due to this very reason, I would like to publish my forthcoming research results in the Bentham Science Publication "Current Topics in Medicinal Chemistry".
S.K Srivastava (The Medicinal Chemistry Department, CSIR-CIMAP, Lucknow (U.P), , India)
Has contributed: QSAR Guided Semi-synthesis and In-Vitro Validation of Anticancer Activity in Ursolic Acid Derivatives
5 Abstract Ahead of Print are available electronically
30 Articles Ahead of Print are available electronically
Tuberculosis (TB) is one of the top 10 causes of death worldwide and the leading cause from a
single infectious agent, ranking above HIV/AIDS. Further, development of resistance against the
frontline anti-tubercular drugs has worsened the already alarming situation. In 2017, 558000 people
(range, 483000-639000) developed TB that was resistant to rifampicin (RR-TB), the most effective
first line drug, and of these, 82% had Multidrug-resistant TB (MDR-TB). The four inexpensive and
effective first lines anti TB drugs (ethambutol, isoniazid, rifampicin and pyrazinamide) were established
nearly fifty years ago.
Although during this period many active compounds underwent clinical trials, but none of them
could get US-FDA approval. After a gap of more than 40 years or so, recently in December 2012, USFDA
accorded approval to the first drug "bedaquiline" for MDR-TB patients who are under treatment
for 2 years or so. Therefore, there is an urgent need of intensive drug discovery to develop new, more effective, affordable and
accessible anti-tubercular agents possessing novel modes of action, which could reduce the time and burden of drug resistant
The recent years have witnessed 4H-1,3-benzothiazin-4-one as a promising class of antimycobacterial agents specially
against resistance TB strain. In this regard Prof. de Souza and Nogueira have presented a detailed review discussing the different
aspects of this chemical class such as synthesis, mechanism of action, medicinal chemistry and combination with other
drugs [1].
DNA gyrase is a clinically validated drug target, currently targeted only by fluoroquinolones class of antibacterials. But in
order to treat serious infections, including multi-drug resistant tuberculosis fluoroquinolones are increasingly being overutilized.
This increases the probability of resistance to fluoroquinolones, which is mediated by a single amino acid change in
gyrA, leading to class wide resistance. The third article of this issue by Dr. Sidharth Chopra and his group provide an overview
on the recent progress in identifying novel scaffolds which target DNA gyrase and provide an update on their discovery and
development status [2].
In this thematic issue, I collected several reviews and research articles contributed by the experts in the area of medicinal
chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, new and
emerging drug targets, natural products, and structure-activity relationships. This issue begins with a research article on "Dihydroartemisinin
and its analogs: A new class of antitubercular agents" by Komal Kalani and Santosh Kumar Srivastava,
reporting for the first time anti-tubercular potential of Dihydroartemisinin (DHA) and its derivatives. Further, synergistic activity
of a DHA derivative was also carried out with frontline anti-TB drugs, which showed synergistic effect with RFM. Therefore,
DHA derivatives have potential for anti-tubercular drug development from an inexpensive and non-toxic natural product
Isocitrate lyase (MtbICL), a key enzyme of glyoxylate pathway has been shown to be involved in the persistence, is an
attractive drug target against persistent mycobacteria. In this regard, Dr. Ashok Sharma and his group have integrated virtual
screening, which resulted in the identification of shinjudilactone (quassinoid), lecheronol A (pimarane) and caniojane (diterpene)
as potential MtbICL inhibitors [4].
Tryptanthrin is a known inhibitor of Mtb enoyl-acyl carrier protein reductase (InhA). In this regard, Prof. Macaev and his
group members modified the structure of tryptanthrin in such a way that it gave a group of 5H-[1,3,4] thiadiazolo [2,3-
b]quinazolin-5-one analogues with varying degree of antimycobacterial activity. The most active compound exhibited superior
inhibition activity (up to 100%) against mycobacterial growth at MIC 6.5 μg/mL and demonstrated a very low per oral toxicity
in animals. He also carried out molecular modeling studies to investigate the binding mechanisms of the synthesized ligands
with InhA [5].
It is known that several imidazole and 1, 2, 4-triazole derivatives possess both antimycobacterial and antifungal activity.
Keeping this thing in mind Prof. Daniele Zampieri and his group members synthesized some 1-(1-(aryl)-2-(2, 6-dichlorophenyl)
hydrazono)ethyl-1H-imidazole and 1H-1,2,4-triazole derivatives and evaluated their antitubercular activity. Among the
series two derivatives showed most promising activity and, according to the docking assessment, the compounds could be
CYP51 inhibitors [6].
In an earlier communication Dr. S.K. Srivastava and his group members for the first time reported anti-tubercular activity in
dihydroartemisinin (DHA-1) against Mtb H37Rv, which prompted him to carry out chemical transformation of DHA into various
derivatives and study their antitubercular potential. Thus, as a part of their drug discovery program in this research article
they semi-synthetically converted DHA into four new acyl derivatives and in-vitro evaluated their anti-tubercular potential
against Mycobacterium tuberculosis H37Rv virulent strain. Two out of the four derivatives showed MIC 12.5 and 3.12μg/mL Further, in silico studies of the most active derivative showed interaction with ARG448 and inhibiting the mycobacterium
enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages.
Finally, this derivative also killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. Since,
dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug
development from a very common, inexpensive, and non toxic natural product [7].
Modern drug discovery has now become largely target-based, where attempts are made to find chemical agents that can hit
the disease-specific enzymes or pathways. In this context, Protein-Protein Interactions (PPIs) have emerged as an interesting
class of targets. Several biological processes, such as cell growth, DNA replication, transcriptional activation, transmembrane
signal transduction, etc., are regulated by multiprotein complexes whose activity and specificity are controlled by proteinprotein
interactions. Thus two issues of this journal have been devoted to highlighting the roles of PPIs. While the previous
issue (Part I) has covered several issues of PPIs such as 'How Cancer Cells Resist Chemotherapy', 'Nanoparticles as Carriers
for Drugs Targeting Protein-Protein Interactions', 'PPI-based Design of Kinase Inhibitors', etc., this second part has highlighted
other roles of PPIs. First, article here is entitled 'Protein-Protein Interaction and Aggregation Inhibitors in Alzheimer's
Disease' and has been written by Ganeshpurkar et al. It presents an update on design and development of drugs based on protein-
protein interactions for the treatment of Alzheimer's Disease (AD), a multifaceted disorder, involving complex pathophysiology
and a plethora of protein-protein interactions [1]. In second article, Cicaloni et al. have presented in detail the applications
of in silico methods for design and development of drugs targeting protein-protein interactions. Several approaches,
models and methods from graph theory are applied to PPIs in order to reveal hidden properties and features of an intricate network
of proteins. Network profiling together with the extraction of knowledge is crucial to better understand the biological significance
of PPIs [2]. In third article entitled 'Protein-Protein Interactions of Phosphodiesterases', Al-Nema and Gaurav highlighted
some of the general characteristics of phosphodiesterases (PDEs) and focused mainly on the protein-protein interactions
of selected PDE enzymes. PDEs are proteins which do not operate alone but in complexes made up of a large number of proteins
which bind to each other via protein-protein interactions [3]. These three articles have highlighted the roles of PPIs in drug
development and might be of great interest to those involved in biochemical and pharmaceutical research. I have equally enjoyed
reading these three articles too and hope so will also the readers.
Modern drug discovery has now become largely target-based, where attempts are made to find chemical agents that can hit
the disease-specific enzymes or pathways. In this context, protein-protein interactions (PPIs) have emerged an interesting class
of targets. Several biological processes, such as cell growth, DNA replication, transcriptional activation, transmembrane signal
transduction, etc., are regulated by multiprotein complexes whose activity and specificity are controlled by protein-protein interactions.
It has been now well understood that various human diseases are associated with aberrant protein-protein interactions.
Among them the notable ones are cervical cancer, leukemia, bacterial infections, inflammation, diabetes, osteoporosis,
and neurodegenerative diseases. Consequently, over the last decades, protein-protein interactions have developed into attractive
molecular targets for the discovery of potential drugs. Thus, drug design targeting PPIs is a burning area and the present two
thematic issues on it present some very interesting articles covering some important aspects of this area.
The very first article in this issue entitled as 'How Cancer Cells Resist Chemotherapy: Design and Development of Drugs
Targeting Protein-Protein Interactions' and authored by Tarasov et al. has discussed the feasibility of predicting general and
specific resistance mechanisms to chemotherapy [1]. The second article authored by 'Athanasios et al. on 'Algorithmic and
Stochastic Representations of Gene Regulatory Networks and Protein-Protein Interactions' presents properties and representations
of PPIs and gene regulatory networks that can be used for the early diagnosis of diseases [2]. In article 3 entitled as
'Quantum Molecular Dynamics, Topological, Group Theoretical and Graph Theoretical Studies of Protein-Protein Interactions'
Balakrishnan and Gupta have reviewed some theoretical studies on PPIs involving hybrid quantum molecular dynamics,
quantum chemical, topological, group theoretical, graph theoretical, and docking studies and discuss how these theoretical studies
facilitate the discovery of PPI inhibitors of therapeutic importance [3]. In article 4 entitled as 'Protein/Hormone Based
Nanoparticles as Carriers for Drugs Targeting Protein-Protein Interactions', authors Al-Suhaimi et al. discuss the use of protein-
based nanoparticles as carriers for drugs targeting protein-protein interactions and also highlight the use of protein hormone-
based nanoscale in health and disease. Protein-protein interactions are of crucial importance in regulating the biological
processes of cells, both in normal and diseased conditions. Recently, significant progress has been made in targeting PPIs using
small molecules and achieving promising results [4]. In article 5, therefore, which is entitled as 'Influence of Amino
Acid Mutations and Small Molecules for Targeted Inhibition of Proteins Involved in Cancer', Kanakaveti et al. have focused on
the advancements in computational research for targeted inhibition of proteins involved in cancer. Kinases are key modulators
in regulating diverse range of cellular activities and are an essential part of the protein-protein interactome [5]. The last article
'Targeting Kinase Interaction Networks: A New Paradigm in PPI-based Design of Kinase Inhibitors' authored by Jenardhanan
et al. presents briefly the structure and function of few important kinases and highlights the protein-protein interaction (PPI)
mechanism of kinases and the kinase specific interactome databases [6]. I have greatly enjoyed reading all these articles and
hope so will do the readers and find them useful for further research on protein-protein interactions.
This issue is related to current trends in enzyme inhibition and activation in drug design.
The topics which are presented deal with prediction of drug-drug interactions, as well as enzymes involved in tuberculosis,
IMPDH enzymes, antimicrobial activity of thiazole-based chalcones and PTP1B inhibitory action and anti-diabetic properties.
The first paper deals with prediction of drug-drug interactions (DDIs) related to inhibition or induction of drug-metabolizing
enzymes. There are three types of DDIs: pharmacokinetic (PK), pharmacodynamic, and pharmaceutical. PK is the most frequent
type of DDI, and often it appears as a result of inhibition or induction of drug metabolizing enzymes (DMEs). In this review,
in silico methods that may be applied for prediction of inhibition or induction of DMEs are summarized and appropriate
computational methods are described for DDI prediction, showing the current place and perspectives of these approaches in
medicinal and pharmaceutical chemistry. Sources of information on DDIs that can be used in pharmaceutical investigations,
medicinal practice and computational models creation are explained in detail and the problem of inaccuracy and redundancy of
this data is discussed. The methods of computer-aided prediction of DDI including the state-of-the-art in physiologically based
pharmacokinetic (PBPK) computational approaches and in protein-based in silico methods dealing with DMEs is provided. In
the section of ligand-based methods is described utilization of pharmacophore models, molecular field analysis, quantitative
structure-activity relationships (QSAR), and similarity analysis applied to prediction of DDIs related to inhibition or induction
of DMEs. Also the problem of DDI severity assessment is addressed highlighting the issues, perspectives and practical use of in
silico methods is discussed [1].
The next paper deals with Mycobacterial tuberculosis enzymes. A literature search has been carried out to find the different
chemical molecules including drugs and their enzyme targets responsible for their antitubercular activities in recent years. This
review provides an overview of the chemical structures with their antitubercular activities and enzyme targets like InhA, ATP
synthase, Lip Y, transmembrane transport protein large (MmpL3), decaprenylphospho-β-D-ribofuranose 2-oxidase, (DprE1).
The major focus has been on the new target ATP synthase. Such an attempt may be useful in designing of new screening using
the Asinex database considering the important three sub-structures of bedaquiline (TMC 207) containing quinoline, tertiary
amine and hydroxyl functionality identifying amodiaquin to have these features but with no antitubercular activity. These studies
were followed by molecular docking using a homology model of mycobacterial ATP synthase and a set of 18 novel substituted
chloroquinolines, belonging to the 2-methyl-4-substituted amino-7-chloroquinolines. This compound library was designed
, synthesized and screened against Mycobacterium smegmatis ATP synthase; 6 compounds (4-9) with the lowest inhibitory
concentration (IC50) values (0.36–1.83 μM) were selected for further in vitro studies. A variety of different compounds such as
benzo[d]oxazol-2(3h)-ones derivatives, pyrrolidinone and pyrrolidines, tetrahydropyrans, methylthiazoles and many others
were synthesized and evaluated against InhA, enzymes involved in the synthesis of mycobacterial cell walls [2].
Another paper is dedicated to design, synthesis, evaluation of antimicrobial activity and molecular docking study of new
thiazole-based chalcones. The designed compounds were synthesized using classical methods of organic synthesis. The in vivo
evaluation of antimicrobial activity was performed by microdilution method. Compounds were tested also against three resistant
strains (MRSA, P. aeruginosa and E. coli). All 28 tested compounds were active showing in some cases better activity than
ampicillin and streptomycin, and all compounds were much more potent than ketoconazole and bifonazole [3].
Docking studies indicated that DNA gyrase, GyrB and MurA inhibition may explain antibacterial activity, while 14-
alanosterol demethylase of CYP51 may explain the antifungal activity.
Another interesting target is Helicobacter pylori IMPDH. Helicobacter pylori infection is one of the primary causes of peptic
ulcer followed by gastric cancer in the world population. Taking into account increased occurrences of multi-drug resistance
to the currently available antibiotics, there is an urgent need for a new class of drugs against H. pylori. Thus, fourteen aryldiazenyl
substituted indoles were synthesized and evaluated against IMPDH. Several lead molecules which could help in a further
endeavor toward identifying selective and potent inhibitors of the Hp IMPDH to fight multi-drug resistance in H. pylori
infections were identified [4].
The last paper is dealing with docking assisted prediction and biological evaluation of Sideritis L. components with PTP1B
inhibitory action and probable anti-diabetic properties. Sideritis L. (Lamiaceae) is a herbal plant growing around the Mediterranean
sea which has been included in the Mediterranean diet for centuries. The antioxidant and anti-inflammatory activity of the
components of Sideritis L. were evaluated previously and the aim of this paper was to investigate the potential of some sideritis's
components to act as PTP1B inhibitors, thus exhibiting beneficial effect in the treatment of diabetes II. Docking prediction
was performed and the components of Sideritis L. were evaluated for their PTP1B inhibitory activity.
Four of the five tested components exhibited inhibitory action. Both an acetoside and lavandulfolioside showed the best
activity with IC50 values of 4.0 μΜ and 9.3 μΜ with competitive and uncompetitive modes of inhibition, respectively [5].
This issue is related to current trends in enzyme inhibition and activation in drug design.
The topics which are presented deal with inhibitors of PTP1B, PDE5A, Alzheimer disease, xenobiotic metabolizing enzymes
as well as caffeic acid derivatives as antimicrobial agents.
The first paper show the attempts made in developing of Protein Tyrosine Phosphatase (PTP1B) inhibitors with high potency,
selectivity and bioavailability and sum up the indications for favorable structural characteristics of effective PTP1B inhibitors.
The research for finding PTP1B inhibitors started with the design of molecules mimicking the tyrosine substrate of the enzyme
and revealed the main requirements for small inhibitors binding to the active site surrounding Cys215. Permanent inhibition
of the enzyme by oxidation of the catalytic Cys215 is also highlighted. Moreover, covalent modification of Cys121, placed
near but not inside the catalytic pocket, has been associated with permanent inhibition of the enzyme [1].
The next review refers to the Acetylcholinesterase Enzyme (AChE), which is the key enzyme in the hydrolysis of the neurotransmitter
acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD, but these drugs provide
only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The review focused on the
development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE),
amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity. Topics covered include
the cholinergic hypothesis, selectivity for AChE over BChE, classification of AChE inhibitors and hybrid strategies. Several
hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates,
and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule.
This is followed by optimization of the activity through structural modifications guided by structure activity relationship studies,
leading to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity
against other above-mentioned targets for further pre-clinical studies [2].
The next review on xenobiotic metabolizing enzymes may find useful applications in related medical interventions or help
in the development of more efficient drugs since xenobiotic metabolizing enzymes are important for the metabolism, elimination
and detoxification of exogenous agents, and are found in most tissues and organs. These are distinguished into phase I and
phase II enzymes, as well as phase III transporters. An extensive review on several aspects of metabolism such as effect of reoxygenation,
stress, resistance to drugs and drug metabolism, restoration of impaired drug metabolism in adjuvant-induced disease,
effect of spironolactone or phenobarbital on cholesterol organ concentrations, interaction of some H1 and H2 receptor
antagonists with cytochrome p450, interaction of ethanol with drugs-involvement of CYPs, induction of CYP4a and peroxisomal
β-oxidation, carbonyl reduction and drug metabolism and effect of selected natural and synthetic compounds on drug metabolism
are presented [3].
The next paper refers to antimicrobial activity of caffeic acid derivatives, selected based on computer-aided predictions.
Twelve tested compounds have shown good antibacterial activity. Five out of twelve tested compounds appeared to be more
active than the reference drugs ampicillin and streptomycin. Despite that all compounds exhibited good activity against all bacteria
tested, the sensitivity of bacteria towards compounds in general was different. The evaluation of antifungal activity revealed
that all compounds were more active than ketoconazole, while seven compounds (2, 3, 4, 5, 7, 8 and 12) appeared to be
more active than bifonazole. Docking results indicate that gyrase inhibition is the putative mechanism of antibacterial action
while the inhibition of 14α-demethylase may be responsible for antifungal action. Prediction of cytotoxicity by PROTOX
showed that compounds are not predicted to be toxic (LD50 1000-2000 mg/kg) [4].
Another inhibitor that are presented in this issue is PDE5A a phosphodiesterase which specifically hydrolyzes the cGMP to
GMP. A simple but efficient route for the synthesis of novel 8–morpholino-2-aryl–2, 5-dihydro-3H-pyrazolo[4, 3-c]quinoline-
3-one derivatives is reported. Molecular docking studies of synthesized compounds with human PDE5A protein shows that all
the compounds exhibited good docking score in comparison with known inhibitors. In addition, all the synthesized molecules
were evaluated against HCT116 cell lines for their antitumor activity. Compounds 5a, 5d, and 6e showed better cytotoxicity
and can be studied as potential inhibitors of PDE5A [5].
The first part of this issue mainly focuses on medicinal developments driven by functional peptides. This part is the continuation of drug
discovery and design, but this time with emphasis on developments driven by functional molecules, especially drugs or their derivatives from
natural products. The selected reviews are summarized as follows:
As a common mental disorder that mainly occurs in 60 years old or elderly people, Alzheimer's disease (AD) is a major threat to public
health system. In the review regarding AD treatment, Wu et al. comprehensively summarized newly reported natural products with anti-AD
activities, including acetylcholine-related natural products, Aβ and tau protein related natural products, antioxidants, anti-inflammatory and
other neuroprotective natural products, as well as NMDA receptor antagonists [1]. Although some natural products show promising preliminary
results in AD treatment, they are still a long way from clinical transformation.
A Chinese scientist Youyou Tu won the 2015 Nobel Prize in Physiology or Medicine because of the outstanding contribution to the discovery
of antimalarial drug artemisinin that is extracted from an herbal prescription. Although artemisinin and its derivatives were primarily
developed as antimalarial agents, later extensive studies have witnessed other pharmaceutical potentials beyond malaria. Thus, the paper of
Liu et al. highlights new pharmaceutical effects of artemisinin derivatives with a focus on the antitumor and antivirus activity [2].
Due to the therapeutic potential of histone deacetylases (HDACs) as one of promising drug targets in cancer, HDAC inhibitors have been
intensively investigated over the last few decades. In the last review, Li et al. explored the developed synthetic and natural HDAC inhibitors
according to different zinc binding groups (ZBGs) and discussed their binding mode with zinc ion in detail, to point the way forward for the
design and development of HDAC inhibitors with novel ZBGs [3].
Finally, we would like to express our sincere gratitude to all authors, reviewers as well as the editorial staff of Current Topics in Medicinal
Chemistry for their kind contributions and excellent support to this issue. Haoxing Wu also acknowledges partial financial support from
the grant of National Natural Science Foundation of China (Grant No. 21602146).
This editorial provides a brief overview of this thematic issue. The thematic
issue is proposed to help medicinal chemists and biologists track the most recent insilico
drug discovery research and high-throughput methods in molecular biochemistry.
Traditional drug design strategy suffers from long periods of time and the high
cost of drug development, which benefits from the recently developed computationbased
drug discovery approaches. These approaches include virtual drug screening,
molecular dynamics, docking and epitope recognition. The collection of this thematic
issue include six articles. The first one reviews the recent advances in in silico B-cell
epitope prediction. The second one proposes a novel improved biogeography-based
optimization and applies it to plant drug extraction. The third one focus on the proteinprotein
interaction network analysis of virulence proteins of Aspergillus fumigatus. The fourth one designs and synthesizes
novel MAO inhibitors with antioxidant potential, and evaluates the former as novel multifunctional agents against
monoamine oxidase A and B. The fifth article critically reviews the various in silico techniques, including 3D QSAR,
COMFA, and molecular docking, for study of the natural product based xanthine oxidase inhibitors. The sixth reviews interactions
between resveratrol and various ligands, and studies that focus on resveratrol using molecular docking strategies.
In the past few decades, the upsurge of various deadly diseases that mar our well being and progression is increasing the
necessity to develop safe and effective theranostic methods. Peptide-based probes are becoming the "state of the art" in targeted
theranostics since they can be conjugated with imaging moieties (e.g. organic dyes, radionuclides, or quantum dots) for targeted
diagnosis and be formed into nanoparticles or biocompatible material for targeted therapy. Further, these probes can provide
biological information at the molecular level during disease process, which is consistent with the concept of precision medicine.
The first part of this present special issue mainly focuses on the recent developments and applications of peptide-based probes
in medicinal chemistry, including peptide design based on machine learning, radionuclide-labeled peptides for cancer imaging
and therapy, peptide-based nanoparticles, and drug delivery for cancer therapy. Although it represents only a small portion of
current research, this issue strives to include several typical and significant topics contributed by extraordinary scholars in frontier
research of this field. We sincerely hope that these reviews foster interest and enthusiasm for functional peptides in theranostic
applications. The papers included in this part can be summarized as follows:
In the opening paper of this issue, Wu et al. systematically introduced machine learning approaches to predict activity of the
peptide, especially antimicrobial peptides (AMPs), anticancer peptides (ACPs) and anti-inflammatory peptides (AIPs), including
contents of peptide-based bioinformatics resources, general workflow of machine learning, and several predictive tools [1].
Compared to traditional screening techniques, this accurate and effective technique will be of great benefit to the discovery of
active peptides.
Due to playing important roles in tumor initiation, progression and metastasis processes and over-expression in many solid
tumor types, C-X-C chemokine receptor 4 (CXCR4) has become a very important target for cancer imaging and therapy. Liu
and co-authors presented the potential of CXCR4-targeted peptides labeled by various radionuclides (such as 111In, 18F, 68Ga
and 177Lu) for the targeted theranostics of CXCR4- positive tumors [2]. Although there were some minor flaws in preclinical
studies, the promising data certainly promoted the translation of these probes to clinical application.
Similarly, prostate-specific membrane antigen (PSMA) is considered a valuable target for both the diagnosis and therapy of
prostate cancer. Diao et al. described a comprehensive overview of the PSMA ligand-based agents for radiotheranostic, especially
those that have been clinically adopted [3]. For treatment of prostate cancer, Zhang et al. demonstrated another method
that is nanoparticle therapy [4]. In their review, different types of therapeutic nanoparticles for prostate cancer, especially those
based on targeting receptors such as PSMA or gastrin-releasing peptide (GRP) were described in detail to provide further understandings
and recommendations on the design and development of targeted nanoparticles. In addition to targeting cancer
cells, specific peptide sequences were also used for the selective identification by a protease when introduced into peptide
chains/linkers or polymer-peptide conjugates, which was an essential part of enzyme-responsive drug delivery systems [5].
Our sincere thanks are due to the editorial staff for their great support during the whole process. Haoxing Wu also acknowledges
partial financial support from the grant of National Natural Science Foundation of China (Grant No. 21602146).
Burgeoning rise in different disease cases such as cancer, viral diseases including Dengue, Chikungunya, Zika,
Ebola, Japanese encephalitis, etc., other tropical and neglected diseases, metabolic conditions such as
diabetes and many other health conditions warrants the need of immediate investigations and end the human
plight for ensuring a better tomorrow.
Advances in scientific research have shown the impact in eradication and prevention of many diseases
conditions such as polio. Interplay of experimental and theoretical approaches have come a long way in proving
their effectiveness and worth in this regard. Earlier computational approaches were almost ignored by a large
section of the scientific community. Last few decades have witnessed a drastic change in the existing beliefs
and today theoretical techniques are not only supporting and supplementing experimental results but also
guiding studies by providing valuable cues.
Computational approaches pertaining to understanding complex biological system have come a long way
during past few years rising from its infancy to blooming into a full-fledged science. Simple bioinformatics and
chemo-informatics approaches are being frequently applied in the arena of system biology and are providing
remarkable insights on unsolved and unanswered scientific questions so far.
Battling diseases requires concerted efforts towards innovation and discovery.
In today's world and time, we face unprecedented challenges of organizing
and prioritizing our strategies against diseases. Development of effective
and commercially feasible therapeutic agents or drugs is a time consuming
and labour–intensive process which thrives on an array of resources. It
is assumed that application of Computer Aided Drug Design (CADD) for
prospecting and profiling of new lead compounds in initial stages of drug discovery
pipeline will offer many advantages both in terms of monetary gain
and optimal use of available resources. Computational chemistry, a combinatorial
subject has come a long way from its initial days of being considered as
an auxiliary science to an indispensable part of most modern drug developmental programs. As the trend shifted from one gene
or protein approach towards the whole genome or proteome analysis in unveiling disease mechanism and progression, computational
approaches slowly but steadily made their way in domain once owned exclusively by medicinal chemists or biologists.
The field has grown by leaps and bounds not only because of advances in computational technology, software development and
processing speed but also because of mammoth scale and rapid pace of generation of experimentally derived data and myriad
types of data available waiting to be analyzed and used. Computational approaches are touching all realms of life and have
catapulted to a position where their crucial role in generating and validating hypotheses, disease identification, knowledge discovery,
therapeutics and control by identification of novel drug targets, drug molecules and vaccines cannot be denied. Some of
the well known applications of computational approaches in drug designing include structure elucidation by molecular modeling,
Quantitative Structure-Activity Relationships (QSAR), docking and molecular simulation, toxicity prediction, machine
learning and data mining approaches for data analysis and visualization.
Considering the huge risks of reemergence and resurgence of infectious diseases and the problem of drug resistance along
with the mounting costs of drug development programs and time gaps, it is only prudent to adopt and integrate computational
techniques and programs in drug discovery pipelines to expedite the progress by turning the scale in our favor by cutting down
costs of such ventures by shortening the drug discovery cycle and reducing efforts, manpower and time duration. Computational
approaches have now become an integral part in storage, management, comparative analysis and in obtaining in-depth
knowledge of disease due to their versatility. Computer aided drug design, genomics and proteomics, metabolomics, interactomics
play a crucial role in mining hidden molecular information, pattern recognition and finally interpretation of biological
significance. Computational chemistry is being widely used at different stages of drug design and production like target identification,
target validation, lead identification and lead optimization in the pharmaceutical industry and has emerged as powerful
tools complementing traditional chemical screening methodology. A synergistic relation between information technology and
routine experimental approaches is required to handle and process voluminous and diverse datasets generated through genomics
and high throughput screening methods and increasing the reliability of the outcomes. Incorporation of techniques based on
artificial intelligence and use of large scale distributed computing for screening have provided a much needed impetus to drug
discovery programs.
Considering the array of disciplines and sub-disciplines involved with computational approaches and vast number of diseases
we are dealing with, the topic requires series of issues to present the recent advancement and understanding on the subject.
Our aim as editors is to bring forth informative articles that highlight the ongoing research in the computational front with
respect to various diseases. We received enormous response and witnessed enthusiasm from the researchers to contribute in this
series of issues. After successful completion of Part-I (Volume 18, Number 13), here we present the Part II (Volume 18, Number
31) with some selected articles summarizing interesting application of the implementation of computational approaches.
The article by Salam et al. focuses on computational structural development and potential inhibitor targeting B-cell lymphoma
2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), which are important targets for lymphoma [1].
Kaur and coworkers reviewed the structural insights required for the inhibition of HIV1 integrase [2].
Novel computational analyses for screening Cryptococcus species have been thoroughly outlined by Manjunath and Skariyachan
[3]. Bashir and coworkers presented a general and overall perspective on the modern theoretical and computational aspects
with respect to human diseases [4].
Kalra and coworkers highlighted the influence of physicochemical properties of functional groups such as ethers and esters
at the 10th position of artemisinin derivatives in optimizing the anti-malarial activity [5]. Tiwari and coworkers reported Acetate
kinase (AcK) as a broad-spectrum novel target in Mycobacterium tuberculosis, Vibrio cholerae, and pathogenic Escherichia
coli [6].
Our sincere thanks are due to Dr. Allen B. Reitz, the Editor-in-Chief of Current Topics in Medicinal Chemistry for providing
us this opportunity of bringing forth this special issue. It has been a great team effort. We would like to express our sincere
thanks to Ms. Ambreen Irshad, Associate Editor and Maria Khan, Editorial Manager. We are thankful to the Editorial staff for
their great support at every step of this issue.
We are sincerely grateful to the authors for their contribution and patience during the review process. Contribution of the
renowned reviewers deserves special mention; we acknowledge their support and efforts in scrutinizing manuscripts and providing
valuable comments and suggestions for improving the quality of manuscripts.
We believe that this special issue will be interesting for the readers of the journal.
Development of novel anti-cancer drugs is one of the most important theme in cancer research. Natural products
and synthetic compounds have been searched extensively to cure different kinds of cancers and still search is on
for finding novel compounds. Great effort has been done to find the target of anti-cancer drugs. Further target
specific compound is being developed to cure cancer. Correlation between structure and function is one of the
important aspects for success of anti-cancer compounds. In recent years strategic drug development program
against the cancer has been initiated including high throughput screening of compound using bioinformatics,
various cell lines, patient-derived tumor xenografts and drug delivery system. The purpose of this special thematic
issue is to summarize the use of ongoing strategy for anti-cancer drug discovery and their valuable contribution for
the expansion in the field of medicinal chemistry.
Microbial Bioinformatics is a rapidly evolving field of study that not only
encompasses health and food science areas, but also presents new opportunities
for advancement and innovation in engineering, manufacturing, and industrial
process improvements [1]. As new sequencing methods become more cost effective
and mobile, obtaining data for analysis is much less the obstacle than it once was [2-4]. The current resistance to widespread
comprehensive data inclusion and diverse applied implementation of findings is the storage and computing power to analyze and organize
raw data into usable and accessible formats. These hurdles will continue to be diminished with the improvement and application
of new and more sophisticated algorithms as the artificial intelligence and cloud computing eases the current technological infrastructure
burdens [5, 6].
The influx of omics data readily available for further analysis should be complemented by advancements in the structural modeling
in order to ensure the structure-function relationships derived are sound. The complementary effect of greater sequence and structural
refinement inputs serve to aid predictive elements as well as engineering of biomolecules, small molecule products, and in silico
systems with medicinal or industrial purposes. Primary sequences dictate later modifications and structure [7]. To properly assess activity
and function, the inclusive treatment of sequence, predicted modifications and corresponding structure, as well as the corresponding
activities of such products in a systems perspective is imperative (Computational systems biology).
Microbial systems have proven to be an invaluable simplistic model in systems biology, however when discussing medical microbiology
in the context of antimicrobial design microbial system inputs are not easily directly transferable to human systems. This aspect
may prove to be an advantage in development of antimicrobials that capitalize on these systematic differences in response to external
perturbation (A network property necessary for concentration robustness.) Longevity, spectrum of coverage, and reduced toxicity
of an antimicrobial treatment prove to be the difference between a theoretically good drug candidate, a later phase failure, and a
true blockbuster global health improvement dictating medication. Precision medicine and pharmacogenomics is becoming more mainstream,
as are more diverse and comprehensive microbial diagnostics becoming more affordable and accessible. The combination of
systems analysis, structure-function relationships of small molecule drug candidates, and experimental findings from high-throughput
screening and structural molecular dynamics validation methods provide improved stepping stones for drug discovery and development
with expanded success limiting toxicity and maximizing the therapeutic effect [8, 9].
The complementation of experimental and computational sciences is ever apparent. As technological advancements in the areas of
sequencing, data storage and acquisition, structural determinations, and systems biology arise, it is ever important that information is
integrated and otherwise built upon for future studies to maximize available resources [10]. Funding, allocation of researchers' time,
and laboratory and computational resources need to be taken into account in order to maximize benefit while limiting redundancies
that contribute to the lag between major findings in academia and their clinical implementation internationally. The academia to clinical
availability factor of medicinally relevant small molecules will continue to improve, as will continually decreasing costs as more
successful, promising leads are distinguished from less favorable leads earlier on and with greater ease in the drug discovery process
[10, 11]. Distinguishing the winners from the losers earlier on in the drug discovery game will continue to contribute to less irrecoverable
costs and less overall risk endured by drug manufactures in order to bring a new drug to market in an attempt to stay ahead of
ever evolving microbial species presenting threats to human health globally, (Drug Delivery: Principles and Applications).
Sortase enzymes are considered to be a powerful taught in all gram positive bacteria as it facilitates several functions including
adhesions, internalins, blood clotting, immune evasion factors and transporters for nutrients across the microbial cell wall envelope.
Due to its receptor availability, it is so called as universal drug target for gram positive pathogens. In present review Chandra Bose
Selvaraj et al. they firmly explained a role of sortase in the virulence of pathogens and were focused on determining the role of Sortase enzymes' involvement in anti-infective studies and also, on the mechanisms of surface protein anchoring to the cell wall envelope
by sortases, and highlight how it plays a strong role as drug target. Now it is considered as a promising target for the development
of new anti-infective drugs that aim to interfere with important Gram-positive virulence mechanisms, evasion of host defenses, and
biofilm formation. Many inhibitors of sortase have been identified using high-throughput or in silico screening of compound libraries,
and also have proved useful tools for probing the action model of the enzyme, several are also promising postulant for the development
into potent inhibitors [15, 16]. These research advances have greatly contributed to our knowledge of sortase cell wall anchoring,
providing a platform for therapeutic targeting and further study in industrial applications.
3. ANTIFUNGAL ACTIVITY, MODE OF ACTION, DOCKING PREDICTION AND ANTI-BIOFILM EFFECTS OF (+)-β-
Candidiasis is a most common fungal infection caused by yeasts that belong to the genus Candida. The antimicrobial activities of
the isomers and enantiomers of pinene were evaluated against bacterial and fungal cells. In present study Ana Cláudia de Macêdo
Andrade et al. exfoliated an example by using biochemistry and in silco approaches through molecular docking simulation and the
effect on the biofilm reduction altogether to summarize, the mechanism of (+)-β-pinene most likely in interfering with the cell wall;
maintain molecular interaction with Delta-14-sterol reductase and, to a lesser extent, with 1, 3-β-glucan synthase; is effective in the
reduction of inhibition of the Candida biofilm [12-13]. (+)-β-pinene antifungal activity for effective to address candidiasis. Further,
toxicological bioassays and phase I and II clinical trials are now needed to investigate the promising antifungal activity of the (+)-β-
pinene as a potential candidate in the treatment of candidiasis which would be an innovative approach.
Plant protease inhibitors (PPIs) are generally small proteins which play key roles in regulation of endogenous proteases and may
exhibit antifeedant, antimicrobial, antifungal, antitumor and cytokine inducing activities. Macrotyloma uniflorum is an unexploited
legume, which is rich in nutrients and promising therapeutic prospects. Manju Mohan et al. in the current study revealed the presence
of a serine protease at active site. Future studies in this direction have to be performed to completely elucidate the characteristic features
of Serine type protease inhibitor seed coat. The presence of protease inhibitor may be the cause for difficulty in human digestion
and it's role in processing antifungal and antimicrobial properties which can be used effectively for its application as a potential sea
food preservative. An economical method to nullify the protease inhibitory activity which will increase the availability of a good protein
source at a cheaper cost, thereby, making it a much needed protein source to meet the middle and lower class necessities [14].
Hyperglycemia associated with diabetes mellitus is a major concern, which affects people with both type 1 and type 2 diabetes and
be controlled by diet management, exercise, anti- hypoglycemic agents, and insulin therapy. Manju Mohan et al. in these current study
evaluates anti-hyperglycemic activity of proteolytic enzymes purification which play central role in the biochemical mechanism of
germination and is intricately involved in many aspects of plant physiology and development [17]. The inhibitory effect of purified
protease on trypsin activity was characterized by enzyme kinetic study.To better understand the mechanism of protein mobilization,
undertaken the task of purifying and characterizing proteases, which occur transiently. The overall study revealed that MUPI is an
insulin sensitizer, and can be considered as a potent bioactive compound for diabetes. This innovative and challenging research will
open up new avenues which constitute an effective anti-hyperglycemic protein which may find application in treatment of diabetes
without evident toxic effects [18].
Signal transducer and activator of transcription 3 [STAT 3] plays major role in cell signalling pathways, but over expression of
this protein leads to osteosarcoma. STAT 3 is a latent cytoplasmic transcription factor which promote oncogenesis. STAT3 appears to
be an important mediator of chemo resistance in osteosarcoma. Ravina et al. in the present study focus on decreasing the over expression
of STAT3 protein by down regulating the pathway using chemical inhibitor to suppress STAT3 activity. Initial approach is made
via in silico method based on docking studies and pharmacophore profiling to identify best pre-established compound [19-27].
Moreover a compound Sorafenib found to be best established drug with effective affinity towards the targeted protein. Interestingly,
on further virtual screening investigation the total energy of virtual screened compound Pubchem CID-44815014 is better than the
entire set of pre-established inhibitors with preferable affinity and inhibitory action. The study foresee Sorafenib and 44815014 are
structurally cognate. Howbeit Sorafenib is efficient inhibitor, but novel compound 44815014 with great affinity towards STAT3 can
be emerge as an important drug in treatment of disease the future ahead. Although, this research will open up new horizons to deliberate
further utilization in in vivo and in vitro analysis. This research will contribute in determining the most effective chemical prospective
to fight against osteosarcoma.
CD20 is a hydrophobic phosphoprotein commence on the surface of the human B lymphocyte cells, and play an essential role in
the proliferation and differentiation of b-cells giving rise to humeral immune response, emerged as a tantalizing therapeutic option for
the treatment of CLL. Kritika et al. in her study emphasis on determining drug which target chronic lymphocytic Leukemia (CLL) by
constrain the activity of CD-20.Author rationalize the interaction of the CD20 with its pre-established inhibitors for CD-20 and to render the new compound having high binding consonance against the target protein. By virtue of Insilco approaches which includes
depiction of targeted protein structure and validation by Ramachandran Plot [27-30]. Further docking studies carried out in addition
with pharmacophore and ADMET analysis for toxicity [31-32]. Withal, conspicuous from the docking studies of pre-established and
virtual screening [33-35] compound for CD-20 resulted in among all compounds top side with PubChem Id 36462 found to have good
affinity among all pre-established compound for desired protein receptor CD-20, whereas on compelling this study virtual screened
compound with PubChem CID-11753896 is inimitable for pharmacokinetics and it is preferable to pharmacological profile to prevent
CLL cancer. This innovative and challenging research will open up new avenues which constitute an effective protein CD-20 which
may find application in treatment of Chronic Lymphomatic Leukemia without evident toxic effects.
Epigenetics is the heritable change in gene function that does not involve changes in the DNA sequence.
To date, several types of epigenetic changes have been characterized, including methylation,
hydroxymethylation, acetylation, phosphorylation, ubiquitination, neddylation and so on. Most of
these modifications can be read, written and erased on DNA, RNA and histone by specific modifiers.
With the biological investigations of these modifiers, some of them are identified as promoters in the
process of various diseases, such as cancer, cardiovascular disease and virus infection. Hence, targeting
epigenetic modifiers has been considered as a promising strategy for disease treatment. To date,
several epigenetic targeted drugs have entered clinic trials, or are currently being used in clinic, including
a DNA methyltransferase inhibitor, bromo domain reader inhibitor, and histone acetylase or deacetylase
inhibitor, histone methyltransferase or demethylase inhibitor, deubiquitinase inhibitor and neddylation
inhibitor. Most of these drugs are applied in leukemia, lymphoma therapy, or are combined with other drugs for the
treatment of solid tumor.
This issue provides the up-to-date summary on some epigenetic targets and the development for related inhibitors for cancer
therapy. The first review by Prof. Zigang Li and co-authors comprehensively summarized the biological roles of epigenetic
targets and related inhibitors developed for cancer therapy. The second review by Prof. Weisheng Feng et al., comprehensively
summarized the recent advances on the development of inhibitors targeting epigenetic targets, particularly those in clinical trials,
and also gave their perspectives on the specificity, limitations and drug combination. The third review by Dr. Fanghui Lu et
al., discussed HDAC inhibitors regarding their functional mechanism, the anti-tumor effects and potential clinical applications.
The fourth review by Prof. Hao Fang et al., summarized recent advances on the structure and functions of HDAC6, and selective
HDAC6 inhibitors. The last review by Prof. Feng Liu et al., summarized an array of nucleoside and non-nucleoside inhibitors
of DNMTs, as well as their biological activities.
I am grateful to all the researchers that contributed to this special issue and the referees for their insightful comments.
The important steps involved in the process of drug discovery are lead identification, lead optimizations, pre-clinical lead
development, and clinical lead development. The contribution of computational design methods to lead identification and optimizations
is no longer a matter of dispute. Exploitation of computational tools has not only reduced the cost but also the time
in drug discovery. The last decade witnessed significant contributions of computational tools in many emerging areas of drug
discovery viz. pharmacokinetics/pharmacodynamics, bioimaging, personalized medicines through system biology and drug repurposing.
This special issue aims to cover the full spectrum of computational approaches relevant for drug discovery.
Let us now discuss the content of this issue. The first review article is focused on the identification of drug binding sites and
includes a comparison of three common approaches namely sequence-based methods, structure-based methods and probe-based
Molecular Dynamics (MD) methods to identifying drug binding sites.
Second review article is also related to hotspot/binding-site identification on protein surfaces, but this review article extensively
talks about challenges and utilities of probe-based Molecular Dynamics (pMD) methods for the identification of small
molecule binding sites.
Third review article focus on current advances in the Fragment-based Drug Design (FBDD) approach.
The subject of the following review article focusses on current status of application of ligand and structure-based approach
targeting Anthrax virus.
The last manuscript is a research article related to ligand and structure-based investigation of structural requirements for
silent information regulator 1 [SIRT1] activation.
The important steps involved in the process of drug discovery are lead identification, lead optimization, pre-clinical lead
development, and clinical lead development. The contribution of computational design methods to lead identification and optimization
is no longer a matter of dispute. Exploitation of computational tools has not only reduced the cost but also the time in
drug discovery. The last decade witnessed significant contributions of computational tools in many emerging areas of drug discovery
viz. pharmacokinetics/pharmacodynamics, bioimaging, personalized medicines through system biology and drug repurposing.
This special issue aims to cover the full spectrum of computational approaches relevant for drug discovery.
Let us turn now to the content of this issue. The first review article talks about epidemics of viral diseases that adversely
affects human population and the role of bioinformatic and immunoinformatic tools which can aid in vaccine design against
these deadly diseases [1].
The second article is a review related to the recent advances and limitations of current pharmacokinetic modeling approaches
and reveal some possible solutions to improve the applicability of in silico Caco-2 permeability models for absorption
property profiling [2].
The subject of the following review article deals with the molecular modeling approaches for the prediction of pharmacokinetic
properties [3].
Fourth review article offers us a vision on computational methods for binding mode and binding affinity prediction of peptide-
MHC complexes [4].
The last manuscript is a research article related to lipid lowering, anti-oxidant and anti-hyperglycemic activity of oxopropanylindole
hydrazone derivatives [5].
The interaction of with Medicinal Chemistry of new Enabling Technologies such as OMICS, Chem-Bioinformatics, etc., is expected to
have a positive impact on the discovery of more effective and safe drugs. In this connection, Current Topics in Medicinal Chemistry journal is
publishing a series of special issues entitled "New experimental and computational tools for drug discovery" to discuss all implications of this
interaction in the broader sense. The series have published a total of four special issues up to date (1-4). The present issue is entitled: New
Experimental and Computational Tools for Drug Discovery: Medicinal Chemistry, Personalized Medicine, Ethical, & Legal Issues. Part - V.
In this sense, the issue presents a new collection of papers exploring the use of new methods of Medicinal Chemistry and Enabling Technologies
in Drug Discovery. The issue also discusses the new aspects emerging from the interaction of Medicinal Chemistry with Personalized
Medicine towards the development of safer personalized drugs in the future. In this connection, the issue also discusses not only chemical and
technical methods but also ethical and legal concerns. The papers included in this part five can be summarized as follows:
Clendenen & D'Alessandro pointed out that metabolomic analysis has made substantial contributions to the understanding of diverse
pathological processes and has the potential to improve diagnosis and identify novel therapeutic targets. As early success in perinatal medicine,
nutrition, chronic diseases, cancer and trauma demonstrates, metabolomics is approaching feasibility in terms of guiding improvement in
population level diagnosis and treatment. This review covers key advancements in clinical metabolomics and applies a high throughput metabolomics
method as a proof of principle to identify novel metabolites associated with remote ischemic preconditioning [1].
Malik et al. focused on the development of xanthine oxidase and monoamine oxidase inhibitors leading to important breakthroughs in the
therapy of oxidative damage, hyperuricemia, gout, neurological, neuropsychiatric disorders and management of reperfusion injury. Drugs
obtained from natural sources play an important role in treatment of various pathological disorders and act as lead compound for the discovery
of new synthetic drug substances. In this review various pharmacological effects produced by inhibition of xanthine oxidase and monoamine
oxidase through natural and synthetic flavanoids as well as anthraquinones are discussed in detail. In this review, all the in-vitro and
other computational approaches are critically discussed which provided the clue about structure activity requirements for further precise
modifications on the basic scaffold [2].
Duardo-Sánchez & De Miguel Beriain highlighted that Medicinal Chemistry and Personalized Medicine related to it, has received a great
attention in recent years. Significant investment and remarkable researches surround the matter; however, not all those promising advances
are reaching patients as quickly as they should. The absence of an adequate regulatory framework could be not helping. The complete and/or
massive sequencing of individual genomes faces many ethical-legal challenges. Some of them are the access to Personalized Medicine; the
treatment of a large volume of sensitive information and the use of tools produced by "big data" systems in clinical care or in predictive models.
In addition, the legal protection of personal data related to health, the exercise of autonomy by patients, closely related to the regulation
regarding clinical trials, are seriously involved. The purpose of this work is to review the regulations of the European Union, in this regard
Sharma et al. pointed out that Renal Cell Carcinoma is a common type of renal cancer-causing deaths worldwide is characterized by sustained
angiogenesis. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous
cell. Signal transduction networks originated by VEGFA/VEGFR2, (a notable ligand-receptor complex in the VEGF system) leads to major
angiogenesis events ranging from endothelial cell proliferation, to new vessel formation. Furthermore, differential expression of VEGFVEGFR
mRNA also found in different types of RCC. The aim of present study is to inhibit the VEGFR2 protein by the action of certain inhibitors
and find the best one. A total of 23 potential inhibitors were searched and used to target the protein using the concept of molecular
docking. The compound SCHEMBL469307 predicted have a high potential to inhibit the VGFR2 protein and can be backed for future studies
in Renal Cell Carcinoma [4].
Ferreira et al. discussed that the increase in the prevalence of drug-resistant pathogens occurs at a time when the discovery and development
of new antimicrobial agents occur slowly. In this context, the objective of this study was to investigate the antifungal activity of
isoeugenol, a phenylpropanoid, by in vitro and in silico assays against Penicillium citrinum strains. For in silico analysis, the software PASS
online, Molinspiration and Osíris were used. For the determination of Minimum Inhibitory Concentration (MIC) and Minimal Fungicide
Concentration (MFC) of isoeugenol and voriconazole were carried out using the broth microdilution technique. PASS online has shown that
isoeugenol has the opportunity to present antiseptic, antifungal, antibacterial, antimycobacterial activities. Molinspiration showed that the
phytoconstituent has good potential for oral bioavailability. The MIC of isoeugenol varied between 256 and 32 μg/mL, MIC50 of 64 μg/mL
and MIC90 was 128 μg/mL. After analysis, it was verified that the isoeugenol have bactericidal effect against the strains of P. citrinum [5].
Infectious diseases, such as endocarditis, chronic skin infections, middle ear infections and sinusitis
are responsible for over 15 million deaths a year [1]. The high mortality rate is due to the widespread
use of antibiotics in humans which cause increased resistance by bacterial strains. Microorganisms can
induce antibiotic resistance by several mechanisms: hydrolysis or chemical modification of the antibiotic
through the production of enzymes, alteration of the antibiotic target site, decrease in membrane
permeability and/or increase active efflux of the antibiotic, and modification of the metabolic pathways
to circumvent the antibiotic effect [2]. Moreover, bacteria in biofilms communicate by means of
molecules, which activate genes responsible for the production of virulence factors (quorum sensing
mechanisms). Current antibiotic therapy is generally effective against free-floating bacteria while it is
often unproductive against pathogens forming biofilms because biofilm colonies can be up to 1000
times more resistant to conventional therapies [3].
Increasing resistance to antibacterial agents has augmented the need for the development of new drugs and drug delivery
approaches to treat infections [4, 5]. Investigations concerning the development of novel strategies to overcome antibiotic resistance
represent a great challenge for both the academic world and industry since bacterial infections represent a significant issue
that includes several areas such as public health or food contamination [6, 7].
This issue highlights the chemical and pharmacological features of novel compounds to treat antibacterial infections and
recent therapeutic approaches to overcome antibiotic resistance. The papers included in this special issue confirmed the importance
of both well-known natural products with low molecular weight and antimicrobial peptides in the management of chronic
and nosocomial infections. However, natural antimicrobial peptides and polyphenolics derivatives could suffer from chemical
instability, photosensibility, and enzymatic degradation, which hamper their clinical use. Here, to overcome these limitations,
medicinal chemistry approaches, such as chemical modifications, replacement of hydrolysis sensible groups or introduction of
mimetics of natural amino acids, were analyzed and reported. Thus, this special issue collects latest advances in the field of
antibacterial drug discovery and delivery such as the use of natural-based antibiofilm and antimicrobial peptides, naturally occurring
prenyloxyphenylpropanoids, and polyphenolics as suitable clinical tools for the treatment of infections.
The guest editor wishes to thank all the researchers that contributed to this special issue and the anonymous reviewers that,
with their helpful and constructive suggestions and comments, improved the quality of the final version of the papers.
Infectious diseases cause remarkable human suffering, particularly in lowincome
and middle-income countries. Infectious diseases are responsible for
the vast economic burden globally. Efforts are going on to develop effective
and safe therapeutics, however the rapid appearance of drug resistance in human
pathogens, weaken the clinical worth of several current drugs. Therefore,
the discovery of new anti-infectious molecules is highly demanded. This special
issue comprises the up-to-date information on drug development for infectious
diseases. The first contribution presents a review article focused on
small molecules effective against liver and blood stage malarial infection was
contributed by Dr. Singh and her co-workers from Miranda House, University
of Delhi, India. This mini-review article covers library of chemical compounds
effective against blood stage and liver stage malarial infections (i.e.
dual stage activity). The second contribution was received from Prof. Samuel
K. Kwofie and colleagues. This review focuses on the malarial aspartic proteases
known as Plasmepsins (Plms) as novel drug targets and antimalarials
targeting Plms. It further discusses inhibitors of hemoglobin-degrading plasmepsins
Plm I, Plm II, Plm IV and histo-aspartic proteases (HAP), as well as HIV protease inhibitors of plasmepsins. The
group led, Prof. Alo Nag and co-workers from University of Delhi South Campus, India contributed the next review article
about ionophores as potent anti-malarials. This review presents an overview on the state-of-the-art of the relevant literature on
ionophores, and provides insight into the mechanism and prospects of different classes of ionophores as promising antimalarial.
Next, two articles were contributed by Prof. Ramesh Chandra and his team members from University of Delhi North
Campus, India. The biological aspects of heme and its drug interactions with CYP450 have been reviewed. The last
contribution is an research article that presents the designing of a novel indoline scaffold based antibacterial compound and
pharmacological evaluation using chemoinformatics approaches.
We are grateful to all the authors and referees for their valuable support to this special issue.
Research to discover new treatments for infectious disease has developed
as a specialty during the past century. At global level, the burden of the infectious
diseases is growing, particularly in low-income and middle-income
countries, and susceptible populations. Infectious diseases trigger millions of
deaths yearly. Widespread resistance of anti-infectious drugs remains a big
threat, particularly when effective vaccines are not available for most of the
infectious diseases. Subsequently, inventions of new therapeutics effective
against infectious diseases are highly required. This special issue of Current
Topics in Medicinal Chemistry contains the latest updates on molecular
mechanisms, drug targets, drug development for infectious diseases in the
form of high-quality articles from the various parts of the world. The first
contribution presents a review article focused on antibiotics-peptide conjugates
from the research group led by Dr. Rakesh K Tiwari, Chapman University,
USA. This article deals with the advanced information on antibioticspeptide
conjugates (APCs) extensively, as an approach to battle the threat of
multi-drug resistance of bacterial pathogens. The adopted APC strategies and
physicochemical properties that show how they can be used to increase the
antibacterial efficacy are also discussed in detail. Next contribution deals with
chemistry and biology of farnesol and its derivatives was prepared by Dr.
Krishna Mohan Poluri from Indian Institute of Technology Roorkee, India.
This interesting review discusses the biological roles, chemical-biochemical synthesis, metabolic engineering, and crucial biotechnological
uses of farnesol based compounds. The third contribution entitled internet resources for drug discovery and design
was received from Prof. Maria Grishina, South Ural State University, Russia. This comprehensive review highlights the
possibilities of the internet resources for a study of a drug action at the most important stages. Also, a detailed assessment of
advantages of the reviewed internet resources is presented. The fourth article entitled chemotherapeutic potential of monensin
as an anti-microbial agent, presented by Dr. Vinoth Rajendran and co-workers deals with the therapeutic potential of monensin
as a new broad spectrum anti-microbial agent that permits further investigations for clinical use. The last review article on apicoplast
metabolism: parasite's Achilles' heel was contributed by Dr. Manmeet Rawat and co-workers from University of New
Mexico, USA. This article describes the cardinal features of the methylerythritol phosphate (MEP) pathway enzymes and progress
made towards the characterization of new inhibitors. MEP pathway is described as a repertoire of novel anti-malarials and
antibacterial drug targets.
The Guest editors are highly thankful to all the authors and referees for their valuable support to this special issue. Science
and Engineering Research Board (SERB), Govt. of India is acknowledged for financial support (ECR/2015/000448). YK is
grateful to the Department of Science and Technology (DST-SERB), Ministry of Science and Technology, India for financial
support (YSS/2015/001966).
As it has already been stated [1, 2], basic neuroscience research is prevented from instrumentation
into direct clinical application due to several methodological limitations, concerning extrapolation,
penetrability and objectivity of the methods.
In other terms a large part of neurobiological inquiry, including studies of neurochemical pathways,
drug targets and mechanisms remain relatively discrepant from clinical utility. In this special
issue there has been delivered strong evidence on the potential use of tetramethoxyluteholine and umbelliferone
as treatment agents for neurodegenerative and neuropsychiatric disorders. However rather
fundamental pharmaceutical perspective (drug synthesis) have been employed by Dhiman et al. [3]
whilst Theoharides and Tsilioni [4] embrace more medical stance, with an emphasis on the drug target
mechanisms in the cytokine-neuropeptide interactions.
Further there has been achieved remarkable advance into in-vivo imaging of the underlying neurochemical processes in
mental disorders which essentially provide insights beyond the aforementioned limitations of the traditionally adopted neuroscientific
methods [2]. Those are in particular the methods of functional neuroimaging. Most promising progress in the application
of magnetic resonance spectroscopy in the study of the metabolites involved in the pathogenesis of schizophrenia has been
summarized by Dwyer et al. and for functional magnetic resonance imaging results with memory evaluation paradigms in bipolar
disorders by Beshkov et al. [5].
This field of research is linked directly to the studies of novel molecular pathways implicated in various mental disorders
[6, 7].
The bottom line message from our Special Issue is that the advances in applied neuroscience research bring together large
scale experimental data sets spanning from neurochemical to neurophysiological and behavioral levels of explanation which
should gradually aspire towards in vivo real time investigations of the biological substrate behind neurological and psychiatric
Design and development of new drugs is extremely expensive and resource-intensive process. During the past few
decades, computer-aided drug designing/ discovery has played a major role in designing of new drugs in a
cost-effective manner. Computer-aided drug designing utilizes concepts of structural/ chemical biology to efficiently
identify and optimize lead compounds using computational tools and methods. Structure-based and ligand-based
drug designing approaches are commonly employed for virtual screening/ identification of lead compounds or to
improve the therapeutic potential of an existing lead compound. Homology modelling, virtual screening, quantitative
structure-activity relationships (QSAR), density functional theory (DFT), molecular docking, molecular dynamics (MD)
simulation and in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) predictions as well as
systems biology approach aids in the drug development process. This thematic issue is aimed to illustrate the pivotal
role of computational techniques in unravelling the structure-function relationship to understand the molecular
recognition events of target macromolecule with ligand leading to the design of improved lead candidate for the
target receptor.
Applied neuroscience includes contributions and insights from neuro-biochemistry, molecular neurobiology,
neuroimmunology, neuropharmacology and among others.
The present topic embraces a complex multi-dimensional interface between basic neuroscience
innovative study designs, novel molecular and bio-chemical markers and drug targets; advanced computational
technologies and their implementation in clinical neuropsychiatry. It will address as well
the interplay of complex neurobiological factors and psychosomatic disorders
Neglected Diseases are those that affect almost exclusively poor and powerless
people living in rural parts of low-income countries [1]. They sometimes
attract other labels, such as tropical diseases or poverty-related diseases.
Neglected diseases include leishmaniasis (kalazar), onchocerciasis, Chagas
disease, leprosy, tuberculosis, schistosomiasis, lymphatic filariasis, African
trypanosomiasis (sleeping sickness), malaria and dengue [2]. Some are lifethreatening,
while others result in high morbidity and severe disabilities [1, 3].
Currently some of these tropical infections have become a major global
concern, due to serious sequelae; as Zika Virus and Ebola. Also, geographical
distances between continents do not represent a barrier to infectious agents
due to rapid transport. Infected human hosts can travel facilitating epidemics.
The objective for this thematic issue was to report recent studies about different approaches in drug
discovery, which comprises synthesis, semi-synthesis, the search for new targets, natural products,
evaluation of biological activities, and/or theoretical approaches as structure-based approaches, SAR,
QSAR, docking and several cheminformatics methods [2], for investigation and selection of new lead
molecules. These efforts involve several studies to aid the drug discovery of new options for the treatment
of neglected diseases.
Dengue like any neglected tropical disease affects a large part of the world population. In this disease,
the infection is caused by arboviruses transmitted by A. aegypti and A. albopictus mosquito, in
which the most severe manifestation is known as dengue hemorrhagic fever. The infected person presents symptoms characteristic
of fever and rash. Among the ways of fighting dengue by bioactives is the inhibition of NS2B-NS3 protease, inhibition of
protein E, and inhibition of sclerotization of the vector cuticle. The cuticle is indispensable for the survival of the mosquito that
can be compromised through the inhibition of arylalkylamine N-acetyltransferase (aaNAT). In our manuscript entitled Dengue
Virus Inhibition Targets: A Review and Docking Study, in silico tests were performed as molecular docking, functional
density analysis, molecular orbitals energies and of the interactions between the bioactive and the targets studied were analyzed.
However, in addition to discussing the fight against dengue virus infection through different routes, some in silico results
of 27 analogs of myricetin have been presented, which showed action on the cuticle sclerotization mechanism.
Dengue Fever: A Worldwide Threat: An Overview of the Infection Process, Environmental Factors for Global Outbreak,
Diagnostic Platforms, and Vaccine Developments by Hosseini et al, is a review article also focused on Dengue. The
paper covers essential topics including an overview on neglected tropical diseases with specific emphasis on Dengue fever,
mosquito's cycle of life and mechanism of infection, adaptive response, and different stages in Dengue immunopathogenesis.
The current work is also dedicated to the thorough study of Dengue outbreak across the globe with a brief study of tropical and
subtropical regions. Moreover, this review article demonstrates the correlation between the climatic factors and Dengue incidence.
In the manuscript entitled, Discovery of Potent Inhibitors for the Inhibition of Dengue Envelope Protein: An In Silico
Approach, Aarthy & Singh showed a study with the crystal structure of Dengue Envelope protein from the protein data bank
optimized through Schrodinger. The structure based virtual screening based on the co-crystallised ligand has been carried out
with the small molecule libraries and based on the docking score, interaction and energy values, best complexes were selected.
The selected complexes were further taken forward for the conformational stability analysis through Molecular dynamics simulation.
From the results it is evident that the compounds DB00179, Quercetin, Silymarin, Dapagliflozlin and Fisetin could be
novel and potent candidates to inhibit the DENV envelope protein.
Many of the tropical diseases are neglected by the researchers and medicinal companies due to lack of profit and other interests.
The Drugs for Neglected Diseases Initiative (DNDi) was established to overcome the problems associated with these
neglected diseases. According to a report published by the WHO, leprosy (Hansen's disease) is also a neglected infectious disease.
The treatment used until now for leprosy is multi-drug treatment. The complete genome identification of Mycobacterium
leprae makes the research easy to develop target specified drugs for leprosy. Rifampicin, identified as a potent drug, along with
other drugs in uniform multi-drug treatment, has a significant effect when given to leprosy patients at initial stages. These are
effective treatments but a specific drug for leprosy is still needed to be identified. The review of Aamir et al., Recent Advancement
in the Diagnosis and Treatment of Leprosy, highlights the use of modern methods for the identification of leprosy
at its earlier stages and the effective use of drugs alone as well as in combination.
The manuscript of Hazra & Patra entitled Alleviating the Neglected Tropical Diseases: Recent Developments in Diagnostics
and Detection discussed various novel research progresses/advancements made for qualitative and quantitative measurement of infectious load in some diseases like dengue, Chagas disease and leishmaniasis; though further improvements in the
specificity and sensitivity front are still awaited. Strategies to combat the problem of antimicrobial drug resistance in the diagnosis
of NTDs have also been put forward by various research groups and organizations. Moreover, the state-of-the-art "omics"
approaches like metabolomics and metagenomics have also started to contribute constructively towards diagnosis and prevention
of the NTDs.
The aim of the study by Khan and co-workers, Formulation and Characterization of a Self-Emulsifying Drug Delivery
system (SEDDS) of Curcumin for the Topical Application in Cutaneous and Mucocutaneous Leishmaniasis, was to develop
a Self-Emulsifying Drug Delivery System (SEDDS) for the hydrophobic polyphenol pigment curcumin to enable it for its
potential use in cutaneous and mucocutaneous leishmaniasis. The results demonstrated that the SEDDS formulations of curcumin
have the potential to provide a promising tool for curcumin for its use through topical routes in the treatment of these diseases.
Through virtual screening of a chemical library of 15,123 small molecules, analyzed by two programs, four potential inhibitors
of phosphoglycerate mutase 1 from P. falciparum were found by Rios-Soto et al. The study was reported in the manuscript
entitled Virtual Screening, Molecular Dynamics and ADME-Tox Tools for Finding Potential Inhibitors of Phosphoglycerate
Mutase 1 from Plasmodium falciparum. Molecular dynamic analysis revealed that these molecules interact with residues
important for enzyme catalysis and molecule ZINC04343691 provoked the highest structural changes. Physiochemical
and toxicological profiles evaluation of these inhibitors with ADME-Tox method suggested that they can be considered as potential
drugs. Furthermore, analysis of human PGAM-B suggested that these molecules could be selective for parasitic enzymes.
In the manuscript of Thomas & Timson, entitled The Mechanism of Action of Praziquantel: Some Hypotheses; the
authors discussed that there is a critical need to understand the biochemical pharmacology of the praziquantel in order to inform
the discovery of the next generation of anthelmintic drugs.
We, the Guest-Editors, would like to express our gratitude to the many authors who contributed to this special issue, reporting
investigations of various aspects of Recent Advancement against Neglected Diseases.
Heterocyclic rings are considered the pillars of medicinal chemistry because
they are merged into the molecular structure of most of the available
therapeutic drugs in the market. Since the early days of medicinal chemistry,
these rings were known to be important as structural feature responsible for
the relationship between structure and biological activities. Taylor et al. [1]
estimated that approximately six new ring systems are created per year and
that some of these are incorporated into new drugs. According to the authors,
1,2,4 and 1,2,3-triazoles are among the top 100 most frequently used ring systems
from small molecule drugs listed in the FDA orange book sorted by descending
The sub-class of five-membered heterocycle [2-4] is widespread in nature [5] as well as in the
therapeutic arsenal available to treat various diseases [6]. In addition, they have several representative
drugs in the market for the treatment of disease as antifungal, anticancer, antiviral, β-lactamase inhibitor,
anticonvulsant and antibiotic agents [7-11].
This special issue is based on seven manuscripts dealing with recent advances in the application of
triazoles derivatives for treatment against infectious disease.
Forezi et al. [12] reported a review covering synthetic methods that give access to other variations
around the 1,2,3-triazole core. The systematic arrangement in this review explores the possibility of
providing practical guidance to alternatives of this heterocycle. It has been divided into sections according
to the types of starting materials and reactions. Heterocyclic rings having nitrogen atoms are the molecular fragments
mostly used in drug design by using the tools of medicinal chemistry.
Souza and colleagues [13] synthesized a series of naphthotriazolyl-4-oxoquinolines that exhibited potent in vitro antileishmanial
activity involving at least two different mechanisms of action, making them promising lead compounds for the
development of new therapeutic alternatives for leishmaniasis.
Branco and coworkers [14] synthesized a series of naphthotriazolyl-4-oxoquinoline derivatives and tested their activity
against a human breast cancer cell line. Among the compounds tested, a molecule was identified that killed the human breast
cancer cell line MCF-7 with minimal effects on its healthy cell MCF10A. The selectivity observed against breast cancer cells
make the molecule 12c a potential candidate as a novel anticancer drug. The antitumor mechanism involves the inhibition of
glycolysis, diminished intracellular ATP levels, induction of ROS production and triggering of apoptosis. These effects are all
selective for cancer cells, since the healthy cells are unaffected, and these effects can only be attributed to the whole molecule
since different groups do not reproduce the effects.
Reis and coworkers [15] prepared a series of symmetrical 1,4-disubstituted bis-1,2,3-triazoles by double Copper Catalyzed
Azide-Alkyne Cycloaddition (CuAAC) from aliphatic bis-azides and a tetraethylene glycol bis-azide derivative. The novel
compounds were evaluated in vitro for their cytotoxic activity against two human tumor cell lines: human breast adenocarcinoma
(MDA-MB 231) and ovarian adenocarcinoma (TOV-21G). The results showed that some compounds exhibited a better
selectivity index and cell viability comparable with the standard drug doxorubicin. These compounds induced apoptosis in both
tested cell lines. The results suggest that these compounds may be promising prototypes for antitumor agents.
Imbroisi-Filho and coworkers [16] tested several novel triazoles compounds for their putative anticancer activity and one
molecule (DAN94) presented selective effects on cancer cells with minimal effects on non-cancer cells. The anticancer effect
occurs through the disruption of mitochondrial potential which induced the production of ROS, triggering cell apoptosis. In
parallel, cells are arrested on G1/G0 phase of the cell cycle, decreasing the ability of these cells to proliferate. On top of that,
when administered to mice with xenograft tumors, DAN94 strongly reduced tumor growth with no toxic effect. These results
suggested that DAN94 is a good candidate for anticancer drug due to its selective effects on cancer cells and should be tested in
a pre-clinical trial.
Costa et. al. [17] synthesized two series of the compounds containing 1,2,3-triazoles ring in their structures and biologically
evaluated novel inhibitors of HIV Reverse Transcriptase (RT). The results of the biological evaluation showed that all compounds
presented high RT inhibition values and lower or comparable inhibitory concentrations. Thus, new compounds could be
considered lead compounds for the development of new antiretroviral compounds.
Lal and coworkers [18] synthetized sixteen new hybrids and were tested in vitro for their antimicrobial activity. Some of the
tested compounds exhibited promising antimicrobial activity and could be utilized for the development of the new and more
potent antimicrobial drugs. All these publications confirm the importance of triazoles scaffold in the search for new biologically active compounds.
The classical methods of diagnosis in both parasitology and mycology
require microscopic visualization as well as the identification
of the microorganisms using their morphological characteristics. In
addition in the case of fungi, it is necessary to use culture-based
methods. However, these methods are tedious and usually not very
sensitive and require trained personnel to perform them.
Tools for the diagnosis and monitoring of the disease remains a
challenge, since a diagnosis is misleading, erroneous or too slow, hinder
effective treatments. As a result, new and low-cost assays are required to help physicians
to establish an accurate and definitive diagnosis and to modify the strategies to control these infectious diseases.
Alternatively, indirect methods have been developed, such as serology-based assays and more recently molecular-
based assays. In this respect, this CTMC thematic issue includes extensive reviews of updated diagnostic
Recently, molecular techniques based on the amplification of nucleic acids have allowed the development of
sensitive, specific and rapid diagnostic methods, however their high price and the requirement of infrastructures
make difficult to apply them in low-resource countries. Dea-Ayuela et al. have analysed the main advances in the
development of a molecular technique called Loop-Mediated Isothermal Amplification (LAMP) assay for the diagnosis
of malaria, leishmaniasis and Chagas' disease as well as the feasibility of their implementation in developing
countries and its use as point-of-care diagnostic tests [1].
Candida is a fungus that is present in the skin, mouth or intestine of healthy individuals whose growth is controlled
primarily by the immune system. However, in certain circumstances, such as immunosuppression, the infection
spreads to different organs causing an invasive candidiasis. Pitarch et al. compiles an extensive review of the
diagnostic methods applied in the most serious forms of candidiasis, the invasive one, since the rapidity in making
the correct diagnosis is fundamental in the control of the infection and the prognosis of the disease [2].
Infectious diseases are caused by bacteria, viruses, fungi and parasites and are
one of the leading causes of human morbidity and mortality, being also responsible
for huge economic losses in the livestock industry. Among the control measurements
of infectious diseases are the correct diagnosis and the adequate treatment
of patients or/and asymptomatic carrier.
Unlike other pathogenic microorganisms, parasites and fungi are eukaryotic
organisms, so their cells are very similar to human/animals cells, making necesary
to search and develop drugs without side effect or toxicity to the hosts cells.
The fungal and parasitic infections have a wide global distribution, however
the therapeutic arsenal available in the XXI century remains extremely reduced,
this problem is aggravated by the appearance of resistance to conventional treatments. Due to the indifference of pharmaceutical industry,
non-profit organizations, such as universities or research centers, are doing an exhaustive effort in the identification of compounds
with antiparasitic and antifungal activity. There are different approaches in the search for new drugs, such as High-Throughput
Screening Tests (HTS), which allow for the evaluation of thousands of different biological compounds through robotic systems, the
identification of the mechanism of action and subsequent development of compounds with the same mechanism, or computer-aided
design that includes structure-activity studies or virtual screening, among others.
On the one hand, the complexity of the host-parasite system makes that compounds with good activity in in silico and in vitro
models do not correlate with good efficacy in vivo, either because they do not reach the parasite per se (many parasites are intracellular
or are anatomically isolated) or because the parasite has different forms with different responses to the compound.
Since these pathogens have accompanied mankind since many years and hence, there are numerous ethno-pharmacological and
ethno-botanical data that support the use of different plants in the treatment of the infections produce by parasites and fungi. Some of
them are collected in traditional Chinese medicine, Ayurvedic or in the traditions of various indigenous groups from different parts of
the world. Due to the difficulty of accessing conventional drugs in many developing countries, WHO has included among health
strategies the incorporation of traditional medicine (complementary and alternative) to health systems, as long as there are clinical
investigations that guarantee its safety and efficacy.
This CTMC thematic issue includes extensive reviews related to the natural, conventional and advanced pharmacological treatments
of various fungal and parasitic infections.
Passero et al., reviewed several studies to understand how active products obtained from plants can be used in the treatment of
leishmaniosis, with special emphasis on those from Brazil.
Vivancos et al., make an extensive review about the treatment of Giardia intestinalis, from conventional pharmacological treatments
to the use of medicinal plants, probiotics and new formulations with the aim to reduce the appearance of resistance and toxicity.
Several parasites are responsible for diseases in livestock and involve large economic losses. Sanchez-Sanchez et al., examine the
different measures applied in the control of Toxoplasma and Neospora, responsible for abortions in livestock with special emphasis on
chemotherapeutical guidelines taking into account the different stages of the parasite and the safety for the final consumer.
Candida is a part of our habitual microbiota, however in certain circumstances it can behave like an opportunistic pathogen, generating
from skin and mucous infections to serious invasive forms.
González-Burgos & Gómez-Serranillos analyze clinical evidence on the effectiveness of natural products in the vulvovaginal candidiasis,
including essential oils, honey and yogurt or plant extracts.
Finally, Taborda et al., focuses on two of the most important systemic mycoses, paracoccidioidomycosis and histoplasmosis, and
their major characteristics in epidemiology, clinical aspects, treatment and laboratory diagnosis.
To rush to edit a special issue requires a lot of energy, motivation and constancy.
When we started to consider the idea, it seemed a quite complicated
challenge because our day to day struggle, as well as the authors and collaborators,
were already strenuous. However, after many talks and discussions we
decided to start this project. Various factors acted as detonators of our determination.
We believe that the modern University cannot be just a factory of
employees, but of people committed to the community and to the culture. In
this particular case, we speak of the scientific culture but with the widest possible
sense, making it a support of our humanity itself. The implementation of
these foundations configures the hegemony of certain relational and understanding
principles, of a vision of science, the life and the world. Beyond the particular positions and the over-meant local conditions
that envelop all that remains within their reach, the moment we currently live allows us to identify the planetary expansion
of scientific thoughts, risky theoretical and practical approaches. They all acquire countless forms allowing the apparent
difference to be valued and signified. Unraveling this avalanche of progress and events is not only a necessity for knowledge,
but a social urgency in the face of global conditions. As new generations are integrated into science, it is imperative to convey
knowledge to them. This gives a community wherein the other is heard, developing strong links between the old and young
It is now time to analyze the two points of maximum relevance in these special numbers: the focus of the publication and
the target audience. With regard to the first, we have focused on works that sketch modern settings and particular allusions to
topics that under our point of view we consider the most relevant. At this time, we can guarantee that the chosen works include
some of the most avant-garde proposals and initiatives, in tune and synchrony with the spirit of the publication. These articles
are contemporary reflections that reread the present and open horizons beyond rigid and inflexible schemes. But not without
giving up scientific rigor and, above all, the interconnection between different branches of knowledge. The second point to take
into account focuses on the potential audience. When a publication with several authors and points of view assumes an expositive
function it is difficult to specify the limits of that audience without having the idea of each one of the contributors. Such
standpoint offers different approaches, which do not stop evolving, just like the audience itself. As an example, communication
channels, audience profile and continuos increase of the multidisciplinarity make it difficult to homogenize the perspective.
That is why we have tried to guarantee a wide outlook of the subject, seeking to ensure the authors to introduce their subjects
with a general and accessible style and increasing the complexity and depth of the study progressively. We thus guarantee the
possibility that each reader will extract the appropriate information and adjusted to their specific needs.
Let us turn now to the content of this issue. The first manuscript has been reserved for both of us, as editors. Our goal was to
introduce the general subject and make a critical view of the state of the art. We know that the biopolymers are the fundamental
basis of chemical medicine and try to encompass everything is impossible. Therefore, we decided to organize the work focusing
on their interactions with different types of materials (organic and inorganic) and the most technologies used: bulk and microfluidics.
The next article is a review related to the development of new classes of antibacterial drugs. This review is focused on the
worldwide problem provenient from bacterial resistance that will generate 10 millions deaths per year in 2050. The authors
present different topics the reason for the decreased development of antibacterial agents, current strategies in antibacterial drug
development, new mechanisms of action, and clinical development.
The third article focuses on a computational vision on physicochemcial properties of biopolymer-material complexes. It
offers a wide and contemporary vision of computational techniques with the most impact on biomedicine, more specifically: a
combination of machine learning techniques and perturbation theories.
The subject of the following article deals with the mechanical properties of biomaterials. Areas focused on tissue engineering
or bone regeneration are not understood without the knowledge of the mechanical properties of the constituents. In this
study the authors introduce us in the field of rheology by studying and analyzing some of the most important bioceramics in
We shall turn to the next manuscript, a review that is focused on the most relevant colloidal drug delivery systems describing
the effects of surface charge, hydrophobicity on bilogical response and the different strategies to modify the surface of organic,
inorganic and biological materials.
The sixth chapter offers us a vision on the structure and hierarchy of collagen not only from a biological perspective but also
explains its potential applications in medicine.
The seventh article is focused on the function of allyl isocyanate (AITC)-loaded Polylactic-co-Glycolic Acid (PLGA) as
anticancer. The targeting ability was tested in HeLa cells demonstrating more effective anticancer properties compared with
free AITC and their citoxicity was even more pronounced when a anti-EGFR antibody was covalently attached to the NPs surface.
Additinally, the importance of this manuscript is that the proposed system (antibody-functinalized AITC-loaded PLGA
NPs) was especifically located in squamous carcinoma A431 cells in comparison with non-functionalized NPs that were distributed
The last manuscript is a research article related to two new materials for the encapsulation of bioactive compounds as carvacol:
Pectin (PEC) and Aloe-gel (AG). The authors characterize this PEC/AG film for different techniques demonstrating the
optimal concentration to microencapsulate carvacol.
Aims & Scope:
Burgeoning rise in different disease cases such as cancer, viral diseases including Dengue, Chikungunya, Zika,
Ebola, Japanese encephalitis, etc., other tropical and neglected diseases, metabolic conditions such as
diabetes and many other health conditions warrants the need of immediate investigations and end the human
plight for ensuring a better tomorrow.
Advances in scientific research have shown the impact in eradication and prevention of many diseases
conditions such as polio. Interplay of experimental and theoretical approaches have come a long way in proving
their effectiveness and worth in this regard. Earlier computational approaches were almost ignored by a large
section of the scientific community. Last few decades have witnessed a drastic change in the existing beliefs
and today theoretical techniques are not only supporting and supplementing experimental results but also
guiding studies by providing valuable cues.
Computational approaches pertaining to understanding complex biological system have come a long way
during past few years rising from its infancy to blooming into a full-fledged science. Simple bioinformatics and
chemo-informatics approaches are being frequently applied in the arena of system biology and are providing
remarkable insights on unsolved and unanswered scientific questions so far
At present, with the continuous development of bioinformatics, computing
technology has been successfully applied in all aspects of pharmacy and
medicine. Among them, the identification of drug-target interactions, synergistic
drug combinations and drug repositioning based on heterogeneous biological
data and powerful computational models are important topics in computational
biology. Research on these important issues is not only for a better
understanding of the various interactions and biological processes, but also for
the development of new drugs and the improvement of human drugs.
Previously, drug research faced an important problem that was difficult to
solve. Since multiple targets usually involve the same disease, following a single disease, a single target, a single drug paradigm
does not have the desired effect on accelerating drug discovery. Recently, in order to improve drug efficacy and overcome
problems before drug resistance, the development of multi-target drugs has received much attention. It is well known that despite
drug-target interactions, experimental assays for synergistic drug combinations and drug repositioning are very valuable
and have made significant contributions to drug research, but the technical challenges make these experiments time consuming,
expensive and limited to small scale studies.
Surprisingly, computational methods can provide new predictions for experimental scientists and narrow the scope of candidates
to accelerate drug discovery. Therefore, the development of a powerful method for the effective detection of potential
drug-target interactions in a genome-wide manner, synergistic drug combinations and drug-disease associations is urgent. Using
these computational models to obtain potential predictions with higher scores, and implementing biological experiments to verify,
will greatly reduce human and material resources.
The following pages of this issue are seven papers presenting current application of computational techniques in pharmacy and
medicine, representing only a small portion of current research. The following is a brief description of these papers.
In the opening paper of this issue, Muhammad et al. comprehensively presented the latest advances in drug target interaction
identification methods and their use in drug multi-pharmacology [1].
In the second review, Ding et al. summarized the latest advances in computational methods for predicting effective drug
combinations in a number of ways, including various datasets for discovering synergistic drug combinations, feature-based
similarity measures and machine learning methods, as well as web-based methods that reveal synergistic drug combinations. In
addition, the calculation method for predicting effective drug combinations was analyzed and predicted in this article [2].
Zhang et al. discussed current knowledge about ncRNA and network pharmacology-regulated genes involved in pulmonary
arterial hypertension, as well as potential drug targets for pulmonary arterial hypertension [3].
Zhang et al. comprehensively reviewed the drug toxicity prediction studies based on machine learning in recent years, and
compared the performance of the models proposed in these studies in terms of accuracy, sensitivity and specificity, providing
the current state-of-the-art in this field and highlighting the issues in the current studies [4].
Wang et al. outlined the structure-based drug design used in drug discovery and highlighted its recent successes and major
challenges of the current structure-based drug design approach [5].
Hao et al. summarized common methods for using protein-protein interaction networks to aid disease research and drug
discovery, including network topology analysis, identification of new pathways, drug targets, and subnetwork biomarkers for
disease [6].
Dong et al. discussed in detail the progress of parallel acceleration molecular docking software based on different common
high performance computing platforms. Not only is the existing suitable program optimized and ported to the high performance
computing platform, but many novel parallel algorithms are also designed and implemented. In addition, this article focuses on
the techniques and methods used to parallelize docking software and recommended exemplar case studies [7].
We would like to express our sincere gratitude to all authors and reviewers for their contribution to this issue. We would
also like to extend our appreciation to the Editor-in-Chief, Dr. Allen B. Reitz and the editorial staff of Current Topics in Medicinal
Chemistry for their excellent support and providing us with the opportunity to pursue this hot topic issue.
Enabling technologies like Computational Chemistry, Bioinformatics, Combinatorial Chemistry,
Metabolomics, Proteomics (OMICS in general), etc., are expected to speed up the discovery of more
efficient and safer drugs in Medicinal Chemistry. Recently, this journal has launched a series of special
issues focused on this topic. The title of this series of special issues is: New experimental and computational
tools for drug discovery: From chemistry to biology. Four (1-4) special issues are currently
available. In these issues, experts from around the world discuss the state-of-art and/or report new
methodologies. The methodologies focus on organic synthesis of new lead compounds, the in silico
screening of new lead compounds, computational discovery of drugs from natural compounds isolated
from plants, the repurposing of known drugs, re-engineering of cost-effective medicines, nano-systems
for drug release, etc. The present issue is entitled: New experimental and computational tools for drug
discovery: From chemistry to biology. Part 4. Metabolomics, Pharmacokinetics, and Medicinal Chemistry. Part 4 is the continuation
of the series and provides six papers focused on new technologies used in drug discovery, but this time with emphasis
on Metabolomics, Pharmacokinetics, and Medicinal Chemistry. The papers included in Part 4 can be summarized as follows:
Gross et al., [1] point out that metabolomics experiments generate a rich array of complex high-dimensional data. They
suggest that this may, in part, account for past and more recent incomplete replications of previously specified biomarker panels,
especially if not adequately considered. Herein, they identify common impediments challenging the analysis of raw, targeted
Metabolomic abundance data and review methods that may remedy these issues, based on personal experiences and those
of others. In doing so, they propose an analytical pipeline suitable for the pre-processing of data prior to downstream biomarker
González-Domínguez et al., [2] present work focused on intervention and observational trials as complementary tools in
Metabolomics. The authors provide a review of the literature regarding the application of metabolomics in assessing metabolic
alterations with diabetes, diabetic insulin resistance, and provide an oral glucose tolerance test case study to demonstrate the
complementarity of observational and interventional study designs.
Kataria et al., [3] presented a work on the role of morin in Neurodegenerative Diseases (NDDs). NDDs are known to cause
profound effects on families and patients, and a tremendous financial burden on the healthcare system of most populations
worldwide. Morin, being a super antioxidant compound, may help prevent and mitigate such disorders by suppression of Reactive
Oxygen Species (ROS) and through the inhibition of multiple additional targets. In this review, the authors discuss various
neuropathological conditions and their specific target sites that may be relevant to morin's neurobiological mechanisms.
Bueso-Bordils et al., [4] focused on obtaining microbiological and pharmacokinetic predictive equations. They reviewed the
state-of-art in the area and also reported a new study. Multi-Linear Regression (MLR) analysis was carried out in order to accurately
predict physicochemical properties and biological activities on a group of antibacterial quinolones by means of a set of
structural descriptors called topological indices. The aim of this work included developing prediction equations for such properties,
after reviewing the relevant literature on antibacterial quinolones.
De Sousa Eduardo et al., [5] focus on the requirement of research related to new antimicrobial agents, as increasing numbers
of microorganisms expressing antibiotic-resistance are emerging. In this paper, the authors review the topic and also pro- De Sousa Eduardo et al., [5] focus on the requirement of research related to new antimicrobial agents, as increasing numbers
of microorganisms expressing antibiotic-resistance are emerging. In this paper, the authors review the topic and also provide
verification for the activity of a phytoconstituent against Escherichia coli strains ATCC 25922 and Staphylococcus aureus
ATCC 25923. The authors recommend further investigations, utilizing different methodologies assessing whether (+) - α-
pinene may provide an effective compound in future antimicrobial therapy.
Srivastava et al., [6] focused on the inhibition of biofilm and virulence factors associated with Candida albicans by the partially
purified secondary metabolites of Streptomyces chrestomyceticus strain ADP4. Despite several advancements in antifungal
drug discovery, fungal diseases, such as Invasive Candidiasis (IC), remain associated with inordinately high rates of morbidity
and mortality worldwide. In this paper, chemical profiling indicates that ADP4 secondary metabolites contained potentially
beneficial alkaloids, flavonoids, polyphenols, terpenoids and triterpenes. The authors also report other experimental and
computational findings.
Infectious diseases are still one of the main cause of mortality and morbidity worldwide. In addition,
antimicrobial resistance is a well-recognized global threat; hence, necessitates the development of
tough policies to control the spread of disease-causing microorganisms coupled with antimicrobial
stewardship strategies and new therapies to reverse this process. In order to fight against microbial
infections, we need new antimicrobials. Much effort has been infused by the scientific community in
the past to the search of new and potential antimicrobials. Researchers have explored antimicrobials
based on plants, microorganisms, and even synthesized new compounds. This issue deals with the important
developments related to the topic of antimicrobials, especially, plant-based antimicrobials,
β-lactamase inhibitors, new synthetic drugs, and also about the target based drug delivery system in
case of chemotherapeutic agents.
Singh et al. have discussed the importance of plant antimicrobials of the past decade (2007-2017). As plants are the major
contributors of vast number of compounds, the plants have remained the indispensable source of medicine, and thus plant based
antimicrobials are important to be considered. Most of these compounds are produced as secondary metabolites and their medicinal
properties may be beneficial for the human being also. The synthetic chemistry has offered various molecules but most
of these are directly or indirectly related to some plant source. In the current review, they have presented the plant-based antimicrobials
reported between 2007 to 2017. Genera where most of the researchers have concentrated during this period includes,
Thymus, Helichrysum, Quercus, Jatropha, Gnaphalium, Acalypha, and Lippia. Some other miscellaneous gene on which one or
two reports are available include, Conocarpus, Chamaesyce, Bucida, Boehmesia, Pancratium, Artemisia, and Cinnamosma [1].
Wang et al. emphasized the development of β-lactamase inhibitors as potential antimicrobial agents. Horizontal transfer of
the genes encoding metallo-β-lactamases (MBLs) among Gram-negative bacteria pathogens has led to the emergence of drugresistant
pathogens, which now represent a major threat to the human health. It is urgent to develop new antibiotic agents to
fight against antibiotic resistance. Metallo-β-lactamases (MBLs) are an important class of Zn(II)-dependent enzymes that can
hydrolyze almost all β-lactams and render bacteria resistant to antibiotics in the clinic. To date, there are no clinically available
MBL inhibitors although a large number of MBL inhibitors have been identified. In this review, they have highlighted the recent
developments in small-molecule MBL inhibitors in the past decade [2].
Kaur et al. synthesized and characterized a new series of diazenyl chalcones by combining the azo and chalcone moiety
together and evaluated them for antimicrobial and antioxidant potential. Some of the derivatives had shown high antimicrobial
and antioxidant activity as compared to the standard drugs and hence presented new lead compounds for the development of
novel antimicrobial agents [3].
Conventional chemotherapeutics lack the specificity and controllability, thus may annihilate healthy cells while attempting
to annihilate cancerous ones. Newly developed nano-drug delivery systems have shown promise in delivering anti-tumor agents
with enhanced stability, durability, and overall performance; especially when used along with targeting and triggering techniques.
Ahmed et al. traced back the history of chemotherapy, addressing the main challenges that have encouraged medical
researchers to seek a sanctuary in nanotechnological-based drug delivery systems that are grafted with appropriate targeting
techniques and drug release mechanisms. A special focus will be paid towards acoustically triggered liposomes encapsulating
doxorubicin [4].
As a whole, all these papers illustrate the versatility of this topic and highlight the importance of developing new prospection
tools to advance the discovery of new compounds.
I want to thank Bentham Science Publishers especially, the Editor in Chief Dr. Allen B. Reitz, who provided me the opportunity
to contribute this thematic issue on such a topic and also all the editorial members for their continued support and cohesive
interactions. I express my highest gratitude to all the contributing authors for their commitment, subject expertise, dedicated
work, healthy coordination and support to me throughout the issue. I would also like to pay special thanks to all the reviewers
for spending their valuable time on critical analysis of the manuscripts and providing valuable suggestions for further
refining the manuscripts. At last, I am also thankful to all our readers.
Infection or colonization, contrary to what many people think, does not
necessarily imply immediate damage to the host. From birth, beneficial microorganisms
coexist and develop within us for a long time. However, when
such organisms cause damage to the host body, an infectious disease with the
associated symptoms and pathology is contracted. From a clinical point of
view, a pathogen is any microorganism capable of developing as an infectious
disease; where differences in pathogenicity depend on virulence. Infectious
diseases caused by pathogenic microorganisms, such as bacteria, viruses,
parasites or fungi can spread, from person to person, directly or indirectly and
throughout a community.
The studies united in this issue demonstrate the efforts of research to combat such infections and reduce the social cost of
these diseases.
Antimicrobial resistance is a major global concern. Strains of Tuberculosis (TB) resistant to rifampicin and other drugs
challenge patient survival and public health. The World Health Organization (WHO) [1] has issued treatment guidelines for
drug-resistant tuberculosis since 1997, and last updated these guidelines in 2016 based on the assessments of patient data in
both published and unpublished studies. As the first choice for patients assailed by Multiple Drug Resistant Or Rifampicin Resistant
(MDR/RR) strains, WHO recommends a standardized treatment regimen of from 9 to 12 months. Mycobacteria are
characterized as slow-growing bacillus having a cell wall composed of highly lipophilic mycolic acids. The nature of this cell
wall is of most importance to the development of new candidates for anti-tuberculosis (anti-TB) drugs. Mycobacterium tuberculosis
is an intracellular pathogen highly adapted to its natural host: the human. Its cell wall, consisting mainly of mycolic acids,
forms a hydrophobic barrier that confers resistance to both desiccation and discoloration by alcohol or acid. In our review,
entitled Multi-Target Antitubercular Drugs, we reported the discovery of 3 classes of compounds that can simultaneously
interact with more than one target of Mycobacterium tuberculosis.
Increased incidences of Candida infection have augmented morbidity and mortality in the human population, particularly
among severely immunocompromised patients and those having a long stay in hospitals (nosocomial infections). Many virulence
factors and fitness attributes are reported to be associated with the pathogenicity of Candida sp [2]. It can cause infections
ranging from easily treatable superficial type to life-threatening invasive infections. Additionally, it has the capability to infect
humans of all age groups. Indeed, overutilization of broad-spectrum antibiotics has further complicated the scenario by leading
to the emergence of less sensitive Candida strains, especially non-albicans. Despite our developed armamentarium, the diagnosis
and treatment of human fungal infections remain a challenge. The review of Dr. Srivastava and co-workers entitled Emerging
virulence, drug resistance and future anti-fungal drugs for Candida pathogens, focused on the prevalence of Candida
spp. as human pathogens with emerging resistance to existing anti-fungal drugs. Furthermore, factors and mechanisms contributing
to the pathogenicity of Candida spp. and the challenges being faced in combating the devastating infections associated
with these pathogens have been discussed. Also, pros and cons of the current and future anti-mycotic drugs have been analyzed.
Current study assesses the in-vitro antimicrobial activity of the crude extract of D. retusa (whole plant) and its derived fractions
against clinically isolated human pathogenic bacteria and fungi [3]. In the manuscript Evaluation of In-Vitro Antimicrobial
Potential of Daphne retusa Hemsl. against Human Pathogenic Bacteria and Fungi, Dr. Nawab et al. studied D. retusa
as powder dried Extracted with methanol (E1). The study showed that D. retusa had a very good inhibitory action against different
bacterial and fungal strains. All of the extracts were active almost against every microorganism used in the study. E2 has
maximum percent inhibition against bacterial growth while E1 has maximum percent inhibition against fungal growth. Streptococcus
pneumonia was the most susceptible bacteria while among fungi, Gongronella butleri showed the highest susceptibility.
Onion (Allium cepa L.) and garlic (Allium sativum L.) extracts are traditionally used in many cultures as antimicrobial
agents. Nonetheless, there is still a dearth of scientific validation pertaining to the antibacterial and possible antibiotic potentiating
activity of these plants [4]. In the work Onion and garlic extracts potentiates the efficacy of conventional antibiotics
against standard and clinical bacterial isolates of Dr. Mahomoodally and co-workers, decoction as traditionally used and
methanol, ethanol, ethyl acetate, and acetone extracts of onion and garlic were evaluated for their antibacterial activity against
15 bacterial strains (6 ATCC strains and 9 clinical isolates) using the broth microdilution method to establish the minimum inhibitory
concentration. The bacteriostatic and bactericidal actions were determined as compared to conventional antibiotics
(streptomycin and chloramphenicol). Fractional Inhibitory Concentration (FIC) was determined to establish any synergistic
interaction between the extracts and antibiotics using a modified checkerboard assay. The observed antibacterial activity might
be justified due to the presence of high concentration of phenolic compounds in the extracts. This study has provided an opportunity
to establish valuable baseline information on the antibiotic potentiating activity of onion and garlic, which can be further
exploited for the treatment and/or management of infectious diseases.
Some research has shown that Lippia pedunculosa Essential Oil (EOLP) has interesting biological activities. However, its
low water solubility is the main challenge in achieving its therapeutic potential [5]. In this context, Cyclodextrins (CDs) have
been widely used in order to overcome this problem due to their capability to improve the physicochemical properties of drugs.
In this perspective, the main goal of the study of Dr. Menezes et al. entitled Physicochemical characterization and antinociceptive
effect of β -cyclodextrin/Lippia pedunculosa essential oil in mice was to investigate how the improvement in the
physicochemical properties of inclusion complexes (EOLP and β-CD) enhances the antinociceptive effect in mice.
We, the Guest-Editors, would like to express our gratitude to the authors who contributed to this special issue, reporting
investigations in various aspects of Perspectives on Infectious Diseases: Progress and Therapeutics.
The discovery that the members within a protein complex are not only found in close proximity but also talking to
each other has expedited development of both experimental and computational techniques, which are used for
studying protein-protein interactions (PPIs). The former provides information regarding the existence of the
interaction and it also helps on the identification of the interaction interface. In spite of emerging roles of PPIs as
novel drug targets for treatment of various crucial diseases over the past decade the field is still far from having a
holistic understanding of the mechanism of interaction. Therefore, experimental techniques should guide and/or
complement computational studies in order to develop efficient therapeutic molecules having higher affinity and
lower side effects. In this special issue, we aim to summarize recent experimental and computational techniques
used for studying PPIs as well as their possible application on selected biological problems of great significance in
an effort to development of novel drugs that target PPIs. Among many others NF-kB, NSP1, MDXM, GPCRS,
CD-40, BAFF-BAFF-L are some of the systems that have been revised.
Cyclic peptides and peptidomimetic molecules (modified peptides) play
critical roles in natural processes, and can also be synthesized for use as research
tools and therapeutics. Protein-Protein Interactions (PPIs) play central
roles in regulating almost all biological processes across organisms and the
central dogma of biology. Compared to small molecules and antibodies, peptides
are advantageous for targeting PPIs because they maintain conformational
flexibility, can be synthesized using relatively straightforward techniques
and are generally less expensive. However, linear peptides are limited
by poor stability and inefficient cell membrane permeability. On the other
hand, cyclic peptides offer improved metabolic stability, bioavailability and
selectivity compared to their linear counterparts; moreover, cyclic peptides are particularly useful for targeting PPIs because
they maintain these enhanced drug-like properties without compromising bioavailability, as often occurs with linear peptides.
Thus, the development of cyclic peptides and peptidomimetics is of great interest in medicinal chemistry, as evidenced by numerous
investigational and approved cyclic peptide pharmaceutical compounds.
This thematic issue is comprised of six strong papers authored by esteemed colleagues renowned for their work in the field
of medicinal chemistry. The overarching topics covered include cyclic peptides in natural and therapeutic settings, the design of
cyclic peptides, several approaches to synthesize cyclic peptides, and examples of cyclic peptides in biological systems. First,
Rubin and Qvit present the first comprehensive review, analysis and critique of backbone-cyclized peptides, discussing their
design, construction, development, and application. To address the construction of backbone-cyclized peptides, Rubin, Tal-
Gan, Gilon, and Qvit subsequently provide a detailed guide for the conversion of protein active regions into peptidomimetic
therapeutic leads – delineating the identification of PPI sites, the definition of bioactive pharmacophores and the use of backbone
cyclization and cycloscan techniques to develop lead compounds.
Next, Perez reviews additional approaches for design of peptidomimetics and discusses their core properties, while comparing
and contrasting the medicinal chemistry and biophysical approaches for discovery and development. Testa, Papini, Chorev
and Rovero extensively discuss approaches to synthesize cyclic peptides and peptidomimetics, including in depth analysis of
the chemistries required to perform ring closing metathesis, lactamization, copper-catalyzed azide alkyne cycloaddition, and
other cyclization reactions. Following this, Hillman, Nadraws and Bertucci delve into stapled peptides and focus on recent advances
in their use for targeting PPIs therapeutically.
Lastly, Mull, Harrington, Sanchez, and Tal-Gan present examples of cyclic peptides in biological systems through an analysis
of cyclic peptide scaffolds in signal transduction pathways across a spectrum of prokaryotic and eukaryotic organisms as
models for the discovery of novel and broadly applicable therapeutic lead compounds.
It was an honor to compile this timely issue. Thanks to the journal for providing the opportunity for our colleagues and us to
share our perspectives. We hope the readers find this material engaging and useful, and that it will inspire further inquiry and
applied works.
Cancer metabolism is an emerging area of research that offers an opportunity to target specific
metabolic vulnerabilities of cancer cells. Cancer cells undergo oncogene-mediated metabolic
reprogramming in order to meet their energy demands. Cancer cells adapt to their
microenvironment and rewire their metabolism to rely heavily on anaerobic glycolysis, a
phenomenon known as the 'Warburg effect'. In addition, cancer cells get addicted to glutamine and also
up regulate fatty acid synthesis to support their survival and rapid proliferation. Recently, there has
been a resurgence of interest in targeting carbohydrate, amino acid, and fatty acid metabolic pathways for
treatment of cancer and overcoming drug resistance in chemotherapy. Other emerging concepts include
targeting mitochondrial metabolism for the treatment of cancer. The overarching theme of this issue is to
highlight the current application, advances, and emerging concepts in the field of cancer metabolism and
discuss the prospects of metabolic inhibitors as next generation cancer therapeutics. The issue will also
emphasize medicinal chemistry efforts aimed at developing small molecule inhibitors targeting aberrant
cancer metabolism.
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The term "alternative" is employed to describe the test method in association with the principles of
the 3Rs - Replacement, Reduction and Refinement. In accordance with this principle, an alternative
method can be used to replace animal testing, reduce the quantity of animals required for each assay,
or refine an animal testing method to minimize pain and suffering.
There are different platforms available to create alternative methods including in vitro models and
computer-based systems. A few elements may be considered in terms of safety when it comes to the
development of a new drug or biomaterial. First it is important to identify the chemical identity and
the composition, as well as chemical structure, impurities and functional groups, followed by the determination
of the physical chemical properties. As a next step, the kinetics aspects, e.g. absorption,
distribution, metabolism and excretion should be evaluated. The mode and /or mechanism of action or
adverse outcome pathways as well as the chemical and biological interaction must be determined. Finally, the responses found
in alternative assays can lead to a proper safety assessment for drugs and biomaterials without the need for animal experimentation.
Within this context, this thematic issue focused on alternative assays applied to replace animal testing in order to assess the
safety and biological activity of currently available and novel drugs and biomedical devices. The manuscript entitled "Epithelial
organotypic cultures: a viable method to address the mechanisms of carcinogenesis by epitheliotropic viruses" describes the
mechanism of carcinogenesis, a topic that was initially researched mainly in animal models.
In another context, some alternative methods have also been employed in biomaterials, as the authors of "Current Methods
Applied to Biomaterials – Characterization Approaches, Safety Assessment and Biological International Standards" extensively
described. This review shows that using alternative tests for biomaterials has almost replaced animal tests, following an actual
tendency. Finally, the last two manuscripts, "Validation cytotoxicity assay for lipophilic substances" and "Alternative methods
to animal studies for the evaluation of topical/transdermal drug delivery systems" are important both for medicine and cosmetics
formulation, as the authors showed the importance to characterize the lipophilic substances, even a difficult issue in cytotoxicity
assays, and the importance of permeation in cosmetics and medical products.
Overall this special issue has addressed aspects concerning alternative assays applied to replace animal testing in order to
assess the safety and biological activity of currently available and novel drugs and biomedical devices and contain materials
that follow the topics in trends and published worldwide. This issue shows balanced viewpoints of experts contributing to
minimize the use of animal tests, in an attempt to act as a primary reference for industrial, commercial and research perspective
in an extensive field of science.
Head and neck squamous carcinoma (HNSCC) is the sixth most common malignant cancer in the world and it is characterized
by a poor prognosis. In fact, the estimated survival rate is 5 years from diagnosis.
The prognosis of the disease is significantly related to the stage in which the disease is diagnosed. Moreover, the therapies
are too invasive and not very efficient, disfiguring and debilitating the survivor's quality of life which is much compromised.
Nowadays, there is not a reliable and non-invasive method for early diagnosis of oral squamous cell carcinoma and the simple
visual examination of the oral cavity is characterized by low sensitivity and specificity, also because the early stages of oral
carcinogenesis are not associated with clear clinical abnormalities in a significant number of patients.
The current issue of "Current Topics in Medicinal Chemistry (CTMC)" is aimed at reviewing the actual knowledge regarding
the HNSCC in order to cover this field with a broad series of papers. The first review was prepared by an Italian team led
by Fatima Ardito, Giovanni Di Gioia, Mario Roberto Pellegrino and Lorenzo Lo Muzio. The authors describe the role of genistein
as a potential anticancer agent against HNSCC. The second contribution is from Linda L. Eastham, Candace M. Howard,
Premalatha Balachandran, David S. Pasco, and Pier Paolo Claudio. In this case, the authors review the role of dietary phytochemicals
as an alternative approach to prevent HNSCC. The third review, led by Riccardo Concu and Maria Natalia Dias-
Soeiro Cordeiro, deals with the role of the Cetuximab in the treatment of HNSCC. The fourth contribution concerns the Aurora
kinase inhibitors in head and neck cancer; this work was prepared by a Chinese-Japanese team led by Guangying Qi, Jing Liu,
Sisi Mi, Takaaki Tsunematsu, Shengjian Jin, Wenhua Shao, Tian Liu, Naozumi Ishimaru, Bo Tang and Yasusei Kudo. Moving
on, Nicola Sgaramella and Karin Nylander review covers the topic of searching for new targets and treatments in the battle
against squamous cell carcinoma of the head and neck. Concu and Cordeiro present an innovative paper dealing with the development
of a new QSAR model aimed at the identification of new inhibitors for the epidermal growth factor receptor. Finally,
Ardito et al. present a new in vitro study of the inhibition activity of the curcumin against squamous cell carcinoma of tongue.