Author:
Hengphasatporn Kowit,Harada Ryuhei,Wilasluck Patcharin,Deetanya Peerapon,Sukandar Edwin R.,Chavasiri Warinthorn,Suroengrit Aphinya,Boonyasuppayakorn Siwaporn,Rungrotmongkol Thanyada,Wangkanont Kittikhun,Shigeta Yasuteru
Abstract
AbstractParallel 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 (Mpro) 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 Mpro, 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 Mpro. 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 Mpro 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 Mpro sites. Integrated LB-PaCS-MD/FMO provided a more reasonable complex structure for ligand binding at the SARS-CoV-2 Mpro active site, which is vital for discovering and designing antiviral drugs.
Funder
Tsukuba Innovation Arena (TIA) collaborative research program, CREST JST, Japan
Japan Agency for Medical Research and Development
high-performance computing infrastructure project
Japan Society for the Promotion of Science
Second Century Fund (C2F), Chulalongkorn University
Science Achievement Scholarship of Thailand
the 90th Anniversary of the Chulalongkorn University Scholarship
Ratchadapiseksompotch Endowment Fund, Faculty of Medicine, Chualongkorn University
National Research Council of Thailand
Thailand Science Research and Innovation Fund Chulalongkorn University
Institute for the Promotion of Teaching Science and Technology
Center of Excellence for Molecular Biology and Genomics of Shrimp
Molecular Crop Research Unit
Publisher
Springer Science and Business Media LLC
Reference59 articles.
1. Du Toit, A. Outbreak of a novel coronavirus. Nat. Rev. Microbiol. https://doi.org/10.1038/s41579-020-0332-0 (2020).
2. Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720. https://doi.org/10.1056/NEJMoa2002032 (2020).
3. National Center for Immunization and Respiratory Diseases (NCIRD), D. o. V. D. Risk for COVID-19 Infection, Hospitalization, and Death By Age Group. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/investigations-discovery/hospitalization-death-by-age.html (2022).
4. Silveira, D. et al. COVID-19: Is there evidence for the use of herbal medicines as adjuvant symptomatic therapy?. Front. Pharmacol. 11, 1479 (2020).
5. Jiménez-Avalos, G. et al. Comprehensive virtual screening of 4.8 k flavonoids reveals novel insights into allosteric inhibition of SARS-CoV-2 MPRO. Sci. Rep. 11, 15452. https://doi.org/10.1038/s41598-021-94951-6 (2021).