Abstract
Parallel cascade selection molecular dynamics-based ligand binding-path sampling (LB-PaCS-MD) was combined with fragment molecular orbital (FMO) calculations to reveal the ligand path from an aqueous solution to the SARS-CoV-2 main protease (M pro ) active site and to customise a ligand-binding pocket suitable for delivering a potent inhibitor. Rubraxanthone exhibited mixed-inhibition antiviral activity against SARS-CoV-2 M pro , relatively low cytotoxicity, and high cellular inhibition. However, the atomic inhibition mechanism remains ambiguous. LB-PaCS-MD/FMO is a hybrid ligand-binding evaluation method elucidating how rubraxanthone interacts with SARS-CoV-2 M pro . In the first step, LB-PaCS-MD, which is regarded as a flexible docking, efficiently samples a set of ligand-binding pathways. After that, a reasonable docking pose of LB-PaCS-MD is evaluated by the FMO calculation to elucidate a set of protein-ligand interactions, enabling one to know the binding affinity of a specified ligand with respect to a target protein. A possible conformation was proposed for rubraxanthone binding to the SARS-CoV-2 M pro active site, and allosteric inhibition was elucidated by combining blind docking with k-means clustering. The interaction profile, key binding residues, and considerable interaction were elucidated for rubraxanthone binding to both M pro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 M pro active site, which is vital for discovering and designing antiviral drugs.
【초록키워드】 SARS-CoV-2, antiviral drugs, cytotoxicity, docking, protease, antiviral activity, Clustering, molecular, inhibitor, mechanism, binding, cellular, Ligand, Interaction, Pathways, complex, M pro, residues, cascade, protein-ligand interactions, target protein, blind, FMO, flexible, evaluated, provided, exhibited, atomic, interact, the binding affinity, the SARS-CoV-2, 【제목키워드】 SARS-CoV-2 main protease, inhibitor, evaluated,