In silico identification of drug candidates against COVID-19

Abstract

The COVID-19 pandemic has caused unprecedented health and economic crisis throughout the world. However, there is no effective medication or therapeutic strategy for treatment of this disease currently. Here, to elucidate the inhibitory effects, we first tested binding affinities of 11 HIV-1 protease inhibitors or their pharmacoenhancers docked onto SARS-CoV-2 main protease (M pro ), and 12 nucleotide-analog inhibitors docked onto RNA dependent RNA polymerase (RdRp). To further obtain the effective drug candidates, we screened 728 approved drugs via virtual screening on SARS-CoV-2 M pro . Our results demonstrate that remdesivir shows the best binding energy on RdRp and saquinvir is the best inhibitor of M pro . Based on the binding energies, we also list 10 top-ranked approved drugs which can be potential inhibitors for M pro . Overall, our results do not only propose drug candidates for further experiments and clinical trials but also pave the way for future lead optimization and drug design.

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp)

“…Meanwhile, we selected four compoundsremdesivir-TP (−55.00 kcal/mol), theaflavin 3,3 -digallate (TF3) (−77.89 kcal/mol), swertiapuniside (−39.42 kcal/mol), and ATP (−57.83 kcal/mol)-as a control group. Here, remdesivir-TP is the best drug candidate, which was identified in our previous study [46]. TF3 and swertiapuniside were proposed as the top-ranked inhibitors of RdRp in the studies from Singh et al [27] and Koulgi et al [47], respectively.…”

“…Furthermore, the binding energies of the top three polyphenols are better than that of ATP, which also suggests that the top three polyphenols might exert strong competitiveness at the ATP binding site. −57.83 1 The original ligand in 7BV2 and the best-scored potential drug identified by our previous study [46]. 2 The best-scored potential drug identified by a previous study [27].…”

Host Response to SARS-CoV2 and Emerging Variants in Pre-Existing Liver and Gastrointestinal Diseases

“…Major SARS-CoV2 target proteins are the spike or S-protein; two proteases, main protease (Mpro) and papain-like protease (PLpro) enzymes, helicase and RNA-dependent RNA polymerase (RdRp) ( Cavasotto and Di Filippo, 2020 ). Host viral entry receptor ACE2 and host protease TMPRSS2 also have been used as targets ( Wu et al., 2020 ). Availability of crystallographic structure of these target proteins may lead to discovery of new drugs with high specificity.…”

Comprehensive Consensus Analysis of SARS-CoV-2 Drug Repurposing Campaigns

“…Hundreds (if not thousands) of virtual screening campaigns have been reported, describing drugs that could bind to one of the six main therapeutic targets encoded by SARS-CoV-2 or the host’s cell, including the viral receptor binding domain (RBD) of the spike glycoprotein (S protein), main protease (M pro ) and papain-like protease (PL pro ) enzymes, and RNA-dependent RNA polymerase (RdRp), as well as the host cell’s angiotensin converting enzyme 2 (ACE2)—a human receptor serving as the viral entry point—and the transmembrane protease serine 2 (TMPRSS2). 5 Simultaneously, a large number of high-throughput screening (HTS) campaigns have been reported—identifying broadly acting (target unspecific) inhibitors for SARS-CoV-2 virus and/or its specific target proteins. These experimental and computational efforts generated valuable drug repurposing information—although frequently contradictive, thereby requiring rigorous benchmarking, standardization and postprocessing.…”

“…Consequently, an explosion in scientific publications and preprints describing a myriad of computational and experimental drug repurposing studies has emerged. Hundreds (if not thousands) of virtual screening campaigns have been reported, describing drugs that could bind to one of the six main therapeutic targets encoded by SARS-CoV-2 or the host’s cell, including the viral receptor binding domain (RBD) of the spike glycoprotein (S protein), main protease (M pro ) and papain-like protease (PL pro ) enzymes, and RNA-dependent RNA polymerase (RdRp), as well as the host cell’s angiotensin converting enzyme 2 (ACE2)a human receptor serving as the viral entry pointand the transmembrane protease serine 2 (TMPRSS2) . Simultaneously, a large number of high-throughput screening (HTS) campaigns have been reportedidentifying broadly acting (target unspecific) inhibitors for SARS-CoV-2 virus and/or its specific target proteins.…”