Promising SARS-CoV-2 main protease inhibitor ligand-binding modes evaluated using LB-PaCS-MD/FMO
Kowit Hengphasatporn, Ryuhei Harada, Patcharin Wilasluck, Peerapon Deetanya, Edwin R. Sukandar, Warinthorn Chavasiri, Aphinya Suroengrit, Siwaporn Boonyasuppayakorn, Thanyada Rungrotmongkol, Kittikhun Wangkanont, Yasuteru Shigeta
Abstract
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.