In our study, we have considered the possibility of 2-deoxy D-glucose (2-DG) working as an anti-viral drug and its role of a competitive inhibitor of glycolysis pathway. A key stage of the SARS-CoV-2 life cycle is the replication of the viral genome within the infected cells. It is a complex process involving the action of several viral and host proteins in order to perform RNA polymerization, proofreading and final capping. To investigate the antiviral property of 2-DG we have selected four viral proteins which are crucial actors of the replicatory machinery of SARS-CoV-2 as targets. The crystal structural data for these 4 viral proteins PL pro (PDB ID: 6wuu) , 3CL pro (PDB ID: 6lu7) , RNA-dependent RNA polymerase (PDB ID: 7bv1) , and O-methyl transferase (PDB ID: 6wkq) of SARS-CoV-2 are available now. The interaction of 2-DG with all the four antiviral proteins was computationally investigated using PRinMTML-ESS platform () which uses the combination of molecular docking at the binding site of protein followed by all atom molecular dynamic simulation of the best-docked pose in water for determining the stability of the protein-ligand bound structure and finally enhanced free energy sampling for better understand the binding interaction of the ligand with the protein. The same methodology has been used for screening large number of new chemical candidates for 3CL pro in our earlier work and the multi-target multi-ligand approach has been used in our high throughput analysis of literature derived repurposing drug candidates for SAR-CoV-2 that can be used to target the genetic regulators known to interact with viral proteins based on experimental and interactome studies In our study, we have initially analysed the interaction of 2-DG with four viral proteins 3C-like protease (3CL pro ), non-structural protein 16 (Nsp16), papain-like cysteine protease (PL pro ) and RNA-dependent RNA polymerase (RdRp) which take part in replication and translation mechanism. Establishment of the viral replication and transcription complex (RTC) that includes, amongst others, RNA-processing and RNA-modifying enzymes and an RNA proofreading function essential for maintaining the integrity of the >30kb coronavirus genome is crucial for virus replication and thus a promising target for antivirals against SARS-CoV-2. One of such target is 3CL pro which resides in non-structural protein-5 (nsp5). 3CL pro releases majority of the non-structural proteins from polyprotein and is crucial for viral life cycle. It's another role is inhibition of interferon signalling. PL pro releases non-structural protein (nsp1, nsp2, nsp3) and the amino terminus of nsp4 from the polyproteins pp1a and pp1ab. PL pro helps SARS-CoV-2 in evading the host innate immune responses by stripping ubiquitin and ISG15 from host-cell proteins. Therefore, targeting PLpro with antiviral drugs may have an advantage for inhibiting viral replication and also inhibiting the dysregulation of signalling cascades in infected cells that may lead to cell death in surrounding, uninfected cells. 2'-O-methyltransferase plays an essential role in immune evasion. Nsp16 achieves this functionality by mimic its human homolog, CMTr1 which methylates mRNA to enhance translation efficiency. However, Nsp16 requires a binding partner, Nsp10, to activate its enzymatic activity unlike CMTr1. The most important part of the coronavirus RTC is RdRP residing in nsp12 and this viral protein is suggested as a promising drug target as it is a crucial enzyme in the virus life cycle both for replication of the viral genome but also for transcription of sgRNAs. Molecular docking was started with automated generation of gridbox at binding site of the viral proteins PL pro (binding region residues: Asp-164, Gly-163, Cys-111, His-272, Gly-271, Tyr-268) obtained from a study that revealed the inhibitory mechanisms and determined the crystal structure of inhibitor VIR250 and VIR251 in complex with SARS-CoV-2 PL pro . A study by Yang et al. determined the crystal structure of 3CL pro of SARS-CoV-2 in complex with the inhibitor (N3). They have predicted the bonding site of inhibitors (binding region residues: Cys-145 to His-41 cavity) which we have used for the grid generation. Yin et al. determined the crystal structure of polymerase bound to RNA and to the drug Remdesivir. The binding site information of RdRP (Gly-683, Ser-682, Asp-684, Asp-760, Ser-759, Ala-685, Tyr-689, Ser-814, Gln-815) has been obtained from this study and used for grid generation. Rosas-Lemus et al. unravelled the crystal structures 2'-O-methyltransferase, the nsp16-nsp10 heterodimer, in complex with an inhibitor Sinefungin. Sinefungin binds to Nsp-16 at the binding site (ASN-6899, ASP-6897, ASP-6928, ASN-6841, CYS-6913, TYR-6930) which has been used for grid generation. In all the protein ligand combination the best docked pose was found be residing at that particular binding site, whose information we have obtained from crystal structure (Figure ). The binding energy of the best docked pose for 3CL pro -2-DG(6lu7-2-DG), NSp-16-2-DG(6wkq-2-DG), PL pro -2-DG(6wuu-2-DG) and RdRp-2-DG(7bv1-2-DG) are listed in Table . Docking scores were found to be -2.35 kcal/mol for 3CL pro -2-DG(6lu7-2-DG) ). Average RMSD value lower than 0.2 nm clearly shows that all the protein ligand combinations are stable. The hydrogen bonding section plots the number of hydrogen bonds between the ligand and the residues at the binding site of the target. NSp16-2-DG(6wkq-2-DG) is found to have the highest number of hydrogen bonding interaction, six followed by two hydrogen bonding in RdRp-2-DG(7bv1-2-DG) and no hydrogen bonding in PL pro -2-DG(6wuu-2-DG), and 3CL pro -2-DG(6lu7-2-DG) combination (Figure ). In the Interaction Energy section, the non-bonded interaction energies, coulomb and van der Waals interaction energies, between the ligand and protein are plotted for each combination in the platform.