The present outbreak of Covid-19 infection due to SARS-CoV-2, a virus from the coronavirus family, has become a major threat to human healthcare. This occurrence of SARS-CoV-2 is the third highly pathogenic event and large-scale epidemic affecting the human population. It follows the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012. SARS-CoV 2 was first reported in December 2019 and after that it has spread all over the world infecting almost 44 million people till date. Moreover, it has been fatal to more than 1.1 million people. The higher rate of transmission of SARS-CoV-2 compared to the SARS-CoV is most probably associated with S-glycoprotein in the receptor-binding domain (RBD) region. The spike S glycoprotein of coronavirus facilitates the binding to the target cell and hence the efficiency of receptor binding domain(RBD)/ angiotensin-converting enzyme 2 (ACE2) is determinant to SARS-COV 2 transmissibility. It is a high time for all researchers in drug development to develop or repurpose FDA approved drug or an epitope to circumvent the current situation of pandemic. SARS-CoV2 is an envelope virus and it contains a positive-sense single-stranded RNA (ssRNA) genome (26-32 kb). The genomics data of pathogens are very important to obtain information regarding potential targets relevant for therapy or diagnostics. Hence in order to design and develop drug against such viral pathogens, it is necessary to start with data mining of viral genomes. The SARS-CoV-2 genome is made of less than 30000 nucleotides and contains genes for 29 different proteins and 10 open reading frame (ORF). The ORF1ab constitutes two third of the viral RNA and encodes as many as 16 non-structural proteins. Some of the key proteins encoded by this gene are PL pro (NSP2), 3CL pro (NSP5), RdRp (NSP12), and O-methyl transferase (NSP16) which play a vital role in the replication and transcription. The structural proteins such as membrane protein (M), envelope protein (E), spike protein (S), nucleocapsid protein (N) and other auxiliary proteins are encoded in ORF2-10. The RNA gene is packed within the N protein and M, E and S protein make the viral coat. Further the entry protein i.e Spike protein in involved in host cell recognition and binds specifically to the Angiotensin-converting enzyme 2 (ACE2) mammalian receptor. Therefore, for therapeutic approach all the structured and non-structured viral protein can be considered as potential target. However, the non-structured proteins PL pro (NSP2), 3CL pro (NSP5), RNA-dependent RNA polymerase (NSP12), and O-methyl transferase (NSP16) that are responsible for viral replication as well as transcription are more essential to target. Again, the infectivity and transmission capacity of SARS-CoV-2 to host cell depends largely on the S glycoprotein. Preclinical studies have predicted that glucose plays a vital role in replication of SARS-CoV-2. SARS-CoV-2 increases the demand of glucose in cells by upregulating the metabolic processes in host cell. Two such important metabolic processes in human cells are glycolysis and glycosylation. These features may have led to the idea that drugs inhibiting glycolysis and glycosylation might prove efficient in the context of SARS-CoV-2. One of the most widely studied glycolytic inhibitors is 2-deoxyglucose (2-DG), a synthetic glucose analogue in which the hydroxyl group at the second carbon atom is replaced by hydrogen ( Hence, to understand the mechanism in two different competitive pathways of therapeutic action of 2-deoxy D-glucose on SARS-CoV-2 infected hosts, we need to take into consideration its interaction with non-structured viral proteins involved in translation and replication of SARS-CoV-2 on one hand and its inhibition mechanism of the glycolysis pathway. In this work, we have used our fully automated integrated platform Prescience in silico Multi-Target Multi-Ligand Enhance Sampling Screening (PRinMTML-ESS) to determine the mode of therapeutic action of 2-DG in SARS-CoV-2 treatment. PRinMTML-ESS is a combined computational approach where docking, molecular dynamic simulation and the free energy calculations using enhanced sampling methods are used to explore the energetics of target-ligand complexation associated with the protein's or an enzyme's binding site (including the ligand) in an explicit solvent. To explore the antiviral property of 2-DG its binding interaction has been studied using our platform with the non-structured viral protein PL pro (NSP2), 3CL pro (NSP5), RNA-dependent RNA polymerase (NSP12), and O-methyl transferase (NSP16) which plays a major role in replication/translation of virus. The effect of 2-DG on the glycolysis process that converts glucose into ATP has been probed using the same combined computational approach and targeting the enzyme hexokinase that phosphorylates glucose to glucose-6-phosphate. Due the structural similarities between 2-DG and glucose (Scheme 1), it is expected that 2-DG would act as a competitive inhibitor of glucose metabolism and thus might strongly affect the SARS-CoV-2 virus replication and activity, which largely depends on the ATP generated from glycolysis in human cells.