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

Autor: Carney DW; Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States. Electronic address: Daniel.carney@takeda.com., Leffler AE; Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States. Electronic address: abba.leffler@schrodinger.com., Bell JA; Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States., Chandrasinghe AS; Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States., Cheng C; Schrödinger, Inc, 9868 Scranton Road, Suite 3200, San Diego, CA 92121, United States., Chang E; Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States., Dornford A; Schrödinger, Inc, 1 Main St, 11th Floor, Cambridge, MA 02142, United States., Dougan DR; Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States., Frye LL; Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States., Grimes ME; Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States., Knehans T; Schrödinger GmbH, Glücksteinallee 25, 68163 Mannheim, Germany., Knight JL; Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States., Komandla M; Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States., Lane W; Treeline Biosciences, 500 Arsenal Way, Watertown, MA 02472, United States., Li H; Schrödinger, Inc, 9868 Scranton Road, Suite 3200, San Diego, CA 92121, United States., Newman SR; Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States., Phimister K; Schrödinger Technologies Limited, 1st Floor West, Davidson House, Forbury Square, Reading RG1 3EU, United Kingdom., Saikatendu KS; Takeda Development Center Americas, Inc, 9625 Towne Centre Drive, San Diego, CA 92121, United States., Silverstein H; Schrödinger, Inc, 101 SW Main Street, Suite 1300, Portland, OR 97204, United States., Vafaei S; Schrödinger, Inc, 1540 Broadway, New York, NY 10036, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 2024 Apr 01; Vol. 103, pp. 117577. Date of Electronic Publication: 2024 Jan 05.
DOI: 10.1016/j.bmc.2023.117577
Abstrakt: 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: all authors are current or former employees of Takeda Pharmaceuticals, Inc, Schrödinger, Inc, or Treeline Biosciences, Inc. (see affiliations) and may own shares of stock and/or stock options in these companies.
(Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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