Virtual screening and molecular docking studies for discovery of potential RNA‐dependent RNA polymerase inhibitors

Abstract

The current COVID‐19 pandemic is caused by severe acute respiratory syndrome corona-virus 2 (SARS‐CoV‐2) infection. Globally, this pandemic has affected over 111 million individuals and posed many health and economic challenges. Much research effort is dedicated to discovering new treatments to address the associated challenges and restrict the spread of SARS‐CoV‐2. Since SARS‐CoV‐2 is a positive‐strand RNA virus, its replication requires the viral RNA‐dependent RNA polymerase (RdRp) enzyme. In this study, we report the discovery of new potential RdRp enzyme inhibitors based on computer modeling and simulation methodologies. The antiviral ZINC database was utilized for covalent docking virtual screening followed by molecular interaction analyses based on reported hot spots within the RdRp binding pocket (PDB: 7BV2). Eleven molecules, ZINC000014944915, ZINC000027556215, ZINC000013556344, ZINC000003589958, ZINC000003833965, ZINC000001642252, ZINC000028525778, ZINC000027557701, ZINC000013781295, ZINC000001651128 and ZINC000013473324, were shown to have the highest binding interactions. These molecules were further assessed by molecular dynamics (MD) simulations and absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The results showed that all 11 molecules except ZINC000027557701 formed stable complexes with the viral RdRp and fell within the accepted ADMET parameters. The identified molecules can be used to design future potential RdRp inhibitors.