2. Academic Validation
  3. Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design

Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design

  • J Med Chem. 2025 Oct 23;68(20):21330-21345. doi: 10.1021/acs.jmedchem.5c01199.
Atsutoshi Okabe 1,  Daniel W Carney 2,  Michiko Tawada 1,  Thamina Akther 1,  Jumpei Aida 1,  Terufumi Takagi 1,  Douglas R Dougan 2,  Abba E Leffler 3,  Jeffrey A Bell 3,  Leah Frye 4,  Eugene R Hickey 3,  Mallareddy Komandla 2,  Will Tao 2,  Jangir Selimkhanov 2,  Kazuko Yonemori 1,  Edcon Chang 2,  Kumar Saikatendu 2,  Atsuko Ochida 1
Affiliations

Affiliations

  • 1 Takeda Pharmaceutical Company Limited, 26-1 Muraoka-Higashi 2-chrome, Fujisawa, Kanagawa 251-8555, Japan.
  • 2 Takeda Development Center Americas, Inc., 9625 Towne Centre Drive, San Diego, California 92121, United States.
  • 3 Schrödinger, Inc., 1540 Broadway, New York, New York 10036, United States.
  • 4 Schrödinger, Inc., 101 SW Main Street, Suite 1300, Portland, Oregon 97204, United States.
PMID: 41076627 DOI: 10.1021/acs.jmedchem.5c01199
Abstract

The COVID-19 pandemic has highlighted a clear need to ensure rapid and equitable global access to health interventions in preparation for future coronavirus-driven pandemics. Here, we report the discovery of highly potent noncovalent inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus (pan-CoV) Mpro inhibition through computer-aided drug design. Virtual screening led to the identification of a noncovalent hit compound with a piperazine core. Structure-guided scaffold morphing provided a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided designs, with induced-fit of Met49/Met165 and Gln189, resulted in the identification of highly potent compound 30, which exhibits pan-CoV Mpro inhibition and cellular Antiviral efficacy against the SARS-CoV-2 omicron variant. The optimized lead compound 30 was characterized by in vitro ADME/Tox assays and in vivo mouse pharmacokinetics. These findings suggest that compound 30 could be an addition to the repertoire of tools used to support future pandemic preparedness.

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