Exploration of FDA-approved drug interactions with SARS-CoV2 main protease using structure-based virtual screening and MM-GBSA binding free energy methods

Abstract

SARS-CoV2 is the coronavirus strain that causes acute respiratory syndromes or COVID19. It has been infecting around 33,000,000 people and causing 1.000,000 deaths around the world. SARS-CoV2 main protease plays a proteolytic role in producing viral polyproteins essential for virus replication. It is considered as an attractive therapeutic strategy. Drug repurposing approach by identifying and testing current available drugs that may bind and inhibit SARS-CoV2 main protease has been widely applied. Here, we computationally screened 2111 FDA (Food and Drug Administration)-approved drugs to investigate its potential interaction to the 3D crystal structure of SARS-CoV-2 main protease recently solved and deposited in Protein Data Bank (PDB). After virtual screening was performed to obtain the docking score and appropriate binding pose, the physic-based method using Molecular Mechanics combined with Generalized Born Surface Area (MM-GBSA) was further employed to estimate relative free binding energy of protease/drugs interaction (in kcal/mol). We report a list of six FDA-approved drugs that have similar and/or greater binding free energy than a peptidomimetic inhibitor of SARS-CoV2 main protease crystal structure used as a positive control. We observe the similarity of hydrogen bonding interactions with amino acids such as Glu166, Gly143, His164 that appear to stabilize the drug binding with protease providing valuable insights to be explored for further structure-activity relationship study and in vitro as well as in vivo validation. © 2021 Author(s).