The main protease (M pro ) 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 M pro 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.
【저자키워드】 COVID-19, SARS-CoV-2, docking, molecular dynamic simulation, MPro, microbial natural products, 【초록키워드】 coronavirus, Virtual screening, protease, binding free energy, anti-SARS-CoV-2, binding affinity, structure-based design, experiment, molecular, inhibitor, disease, compounds, Interaction, microbial, acute respiratory syndrome, drug candidates, Compound, M pro, table, Final, MDs, performed, applied, provide, complexes, binding mode, calculate, filtered, structural flexibility, 【제목키워드】 natural, M pro, product, Potential,