Open AccessPotent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations
Author(s) -
Chunhui Zhang,
Elizabeth A Stone,
M.G. Deshmukh,
Joseph A. Ippolito,
Mohammad Mehdi Ghahremanpour,
Julian TiradoRives,
Krasimir A. Spasov,
Shuo Zhang,
Yuka Takeo,
Shalley N. Kudalkar,
Zhuobin Liang,
Farren J. Isaacs,
Brett D. Lindenbach,
Scott J. Miller,
Karen S. Anderson,
William L. Jorgensen
Publication year - 2021
Publication title -
acs central science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.893
H-Index - 76
eISSN - 2374-7951
pISSN - 2374-7943
DOI - 10.1021/acscentsci.1c00039
Subject(s) - perampanel , free energy perturbation , chemistry , combinatorial chemistry , protease , covid-19 , ic50 , stereochemistry , enzyme , molecular dynamics , computational chemistry , biochemistry , in vitro , pharmacology , biology , medicine , disease , pathology , infectious disease (medical specialty) , adverse effect
Starting from our previous finding of 14 known drugs as inhibitors of the main protease (M pro ) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC 50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for M pro -ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to M pro . Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.