Microbial Natural Products as Potential Inhibitors of SARS-CoV-2 Main Protease (Mpro)
Ahmed M. Sayed, Hani A. Alhadrami, Ahmed O. El‐Gendy, Yara I. Shamikh, Lassaâd Belbahri, Hossam M. Hassan, Usama Ramadan Abdelmohsen, Mostafa E. Rateb
Abstract
The main protease (Mpro) of the newly emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was subjected to hyphenated pharmacophoric-based and structural-based virtual screenings using a library of microbial natural products (>24,000 compounds). Subsequent filtering of the resulted hits according to the Lipinski’s rules was applied to select only the drug-like molecules. Top-scoring hits were further filtered out depending on their ability to show constant good binding affinities towards the molecular dynamic simulation (MDS)-derived enzyme’s conformers. Final MDS experiments were performed on the ligand–protein complexes (compounds 1–12, Table S1) to verify their binding modes and calculate their binding free energy. Consequently, a final selection of six compounds (1–6) was proposed to possess high potential as anti-SARS-CoV-2 drug candidates. Our study provides insight into the role of the Mpro structural flexibility during interactions with the possible inhibitors and sheds light on the structure-based design of anti-coronavirus disease 2019 (COVID-19) therapeutics targeting SARS-CoV-2.