2. Academic Validation
  3. Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity

Exploiting high-energy hydration sites for the discovery of potent peptide aldehyde inhibitors of the SARS-CoV-2 main protease with cellular antiviral activity

  • Bioorg Med Chem. 2024 Apr 1:103:117577. doi: 10.1016/j.bmc.2023.117577.
Daniel W Carney 1,  Abba E Leffler 2,  Jeffrey A Bell 3,  Asela S Chandrasinghe 4,  Cecilia Cheng 5,  Edcon Chang 6,  Adam Dornford 7,  Douglas R Dougan 6,  Leah L Frye 4,  Mary E Grimes 4,  Tim Knehans 8,  Jennifer L Knight 3,  Mallareddy Komandla 6,  Weston Lane 9,  Hubert Li 5,  Sophia R Newman 4,  Katalin Phimister 10,  Kumar S Saikatendu 6,  Hercules Silverstein 4,  Shaghayegh Vafaei 3
Affiliations

Affiliations

  • 1 Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States. Electronic address: [email protected].
  • 2 Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States. Electronic address: [email protected].
  • 3 Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States.
  • 4 Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States.
  • 5 Schrödinger, Inc, 9868 Scranton Road, Suite 3200, San Diego, CA 92121, United States.
  • 6 Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States.
  • 7 Schrödinger, Inc, 1 Main St, 11th Floor, Cambridge, MA 02142, United States.
  • 8 Schrödinger GmbH, Glücksteinallee 25, 68163 Mannheim, Germany.
  • 9 Treeline Biosciences, 500 Arsenal Way, Watertown, MA 02472, United States.
  • 10 Schrödinger Technologies Limited, 1st Floor West, Davidson House, Forbury Square, Reading RG1 3EU, United Kingdom.
PMID: 38518735 DOI: 10.1016/j.bmc.2023.117577
Abstract

Small-molecule antivirals that prevent the replication of the SARS-CoV-2 virus by blocking the enzymatic activity of its main protease (Mpro) are and will be a tenet of pandemic preparedness. However, the peptidic nature of such compounds often precludes the design of compounds within favorable physical property ranges, limiting cellular activity. Here we describe the discovery of peptide aldehyde Mpro inhibitors with potent enzymatic and cellular Antiviral activity. This structure-activity relationship (SAR) exploration was guided by the use of calculated hydration site thermodynamic maps (WaterMap) to drive potency via displacement of waters from high-energy sites. Thousands of diverse compounds were designed to target these high-energy hydration sites and then prioritized for synthesis by physics- and structure-based Free-Energy Perturbation (FEP+) simulations, which accurately predicted biochemical potencies. This approach ultimately led to the rapid discovery of lead compounds with unique SAR that exhibited potent enzymatic and cellular activity with excellent pan-coronavirus coverage.

Keywords

COVID-19; FEP+; Free-energy perturbation; Main protease; Mpro; Peptide aldehyde; Peptidomimetic; Protease inhibitor; SARS-CoV-2; WaterMap.

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