Scientific Reports (Oct 2022)

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

DOI
https://doi.org/10.1038/s41598-022-22703-1
Journal volume & issue
Vol. 12, no. 1
pp. 1 – 16

Abstract

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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 (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.