Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

Zhang, Chun-Hui; Stone, Elizabeth A.; Deshmukh, Maya; Ippolito, Joseph A.; Ghahremanpour, Mohammad M.; Tirado-Rives, Julian; Spasov, Krasimir A.; Zhang, Shuo; Takeo, Yuka; Kudalkar, Shalley N.; Liang, Zhuobin; Isaacs, Farren; Lindenbach, Brett; Miller, Scott J.; Anderson, Karen S.; Jorgensen, William L.

doi:10.1021/acscentsci.1c00039

Title: Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

Journal Article · Mon Feb 22 00:00:00 UTC 2021 · ACS Central Science

DOI: https://doi.org/10.1021/acscentsci.1c00039 · OSTI ID:1777303

Zhang, Chun-Hui ^[1];

^[1];

^[2]; Ippolito, Joseph A. ^[3];

^[1];

^[1]; Spasov, Krasimir A. ^[2]; Zhang, Shuo ^[2]; Takeo, Yuka ^[2]; Kudalkar, Shalley N. ^[2]; Liang, Zhuobin ^[1];

^[1]; Lindenbach, Brett ^[2];

^[1];

^[2];

^[1]

Yale Univ., New Haven, CT (United States)
Yale Univ. School of Medicine, New Haven, CT (United States)
Yale Univ., New Haven, CT (United States); Yale Univ. School of Medicine, New Haven, CT (United States)

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 IC₅₀ 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS); Brookhaven National Laboratory (BNL), Upton, NY (United States)

Sponsoring Organization:: NIH-ORIP HEI; National Institute of Health, National Institute of General Medical Sciences (NIGMS); USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357; SC0012704

OSTI ID:: 1777303

Report Number(s):: BNL-221443-2021-JACI; APS_261886

Journal Information:: ACS Central Science, Journal Name: ACS Central Science Journal Issue: 3 Vol. 7; ISSN 2374-7943

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Title: Potent Noncovalent Inhibitors of the Main Protease of SARS-CoV-2 from Molecular Sculpting of the Drug Perampanel Guided by Free Energy Perturbation Calculations

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