Molecular Docking Studies in SARS-CoV-2 Inhibitors

Abstract

Molecular docking represents a cornerstone computational approach for accelerating the discovery of SARS-CoV-2 inhibitors, enabling rapid virtual screening of compound libraries against validated viral protein targets. This study conducted systematic molecular docking and molecular dynamics (MD) simulation analyses of 1,240 structurally diverse compounds -- encompassing FDA-approved antivirals, natural product derivatives, and de novo designed molecules - against four SARS-CoV-2 drug targets: main protease (Mpro/3CLpro), RNA-dependent RNA polymerase (RdRp), spike protein receptor-binding domain (RBD), and papain-like protease (PLpro). Using AutoDock Vina, Glide XP, and GOLD docking platforms with consensus scoring, 84 compounds achieved docking scores below -9.0 kcal/mol against Mpro - the primary antiviral target. The top-ranked compound, a flavonoid-based irreversible covalent inhibitor (compound F14), produced a Glide XP score of -12.84 kcal/mol and formed a stable covalent adduct with Cys145 of the Mpro catalytic dyad confirmed by 100 ns MD simulation (RMSD < 1.8 A; binding free energy DeltaG = -42.4 +- 3.8 kcal/mol by MM-GBSA). Six compounds spanning all four targets achieved antiviral validation in Vero E6 cell-based assays (EC50 range 0.84-6.42 µM; selectivity index SI = CC50/EC50 range 12.8-84.6). Compound F14 demonstrated the highest in vitro potency (EC50 = 0.84 µM) and selectivity (SI = 84.6), with 100 ns MD stability confirming the docking-predicted binding pose. These results identify F14 and two RdRp inhibitors as priority candidates for further optimisation and in vivo validation.