Applying polypharmacology approach for drug repurposing for SARS-CoV2

Abstract

Exploring the new therapeutic indications of known drugs for treating COVID-19, popularly known as drug repurposing, is emerging as a pragmatic approach especially owing to the mounting pressure to control the pandemic. Targeting multiple targets with a single drug by employing drug repurposing known as the polypharmacology approach may be an optimised strategy for the development of effective therapeutics. In this study, virtual screening has been carried out on seven popular SARS-CoV-2 targets (3CL pro , PL pro , RdRp (NSP12), NSP13, NSP14, NSP15, and NSP16). A total of 4015 approved drugs were screened against these targets. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected based on the docking score, ability to interact with four or more targets and having a reasonably good number of interactions with key residues in the targets. The MD simulations and MM-PBSA studies showed reasonable stability of protein-drug complexes and sustainability of key interactions between the drugs with their respective targets throughout the course of MD simulations. The identified four drug molecules were also compared with the known drugs namely elbasvir and nafamostat. While the study has provided a detailed account of the chosen protein-drug complexes, it has explored the nature of seven important targets of SARS-CoV-2 by evaluating the protein-drug complexation process in great detail. Graphical abstract Drug repurposing strategy against SARS-CoV2 drug targets. Computational analysis was performed to identify repurposable approved drug candidates against SARS-CoV2 using approaches such as virtual screening, molecular dynamics simulation and MM-PBSA calculations. Four drugs namely venetoclax, tirilazad, acetyldigitoxin, and ledipasvir have been selected as potential candidates. Supplementary Information The online version contains supplementary material available at 10.1007/s12039-022-02046-0.

Identification of a Papain-Like Protease Inhibitor with Potential for Repurposing in Combination with an Mpro Protease Inhibitor for Treatment of SARS-CoV-2

“…The docking data suggests that neither GRL-0617 or DDL-701 (Figure 5A and B, respectively) interacts with the active site cysteine-111 residue, but rather are bound to the site around tyrosine-268 which lies outside the tunnel containing the active site residue Cys111. DDL-715 and the reported PL pro inhibitor losartan [22] bind the enzyme similarly to DDL-701, at the site around Tyr268 and at the entrance of the active site tunnel leading to Cys111 (Supplementary Figures S3 and S5, respectively).…”

“…Recent studies suggest that the virus could develop resistance to nirmatrelvir through development of mutations in the protease M pro , a phenomenon observed with many antiviral drugs [18,19]. This has raised interest in the development of protease inhibitor cocktail therapy for SARS-CoV-2 [20][21][22][23][24][25][26][27] to increase efficacy and reduce the risk of rebound, which is modeled on the use of protease cocktails for the treatment of HIV and hepatitis C. Use of a protease inhibitor cocktail could help reduce or prevent resistance by making it harder for the virus to evolve around multiple inhibitors.…”

Computational screening for investigating the synergistic regulatory potential of drugs and phytochemicals in combination with 2-deoxy-D-glucose against SARS-CoV-2

“…Redocking studies were executed to validate the compounds showing the best binding energy obtained by blind docking. We analyzed the active site residues of all three targets from available literature [ 23 , 24 ] and performed individual ligand docking and MLSD with the above protocol [ 25 , 26 ]. The best poses were selected based on maximum interactions depicted for minimum binding energy conformations, and these interactions between protein–ligand complexes were then visualized using the Discovery studio software.…”

A structure-based drug repurposing approach by considering the twenty four SARS-CoV2 Targets: A consensus scoring approach

“…Several studies have reported that dihydroergotamine and ergotamine are having stable interactions with 3CL pro and also it has the polpypharmacology e cacy [46]. In addition, the drugs tirilazad and venetoclax was reported to show stable binding a nity towards multiple targets for SARS-CoV2 which indicates their polypharmacology property suggesting them as potential candidate for drug repurposing [35,47].…”

“…Four drugs (i.e., venetoclax, tirilazad, acetyldigitoxin, and ledipasvir) were chosen based on the docking scores, binding pose and the interaction pattern with the SARS-CoV2 targets [35]. In arriving at the drug repurposing a consensus scoring approach has been adopted [36].…”