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Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor

  • Jens Glaser*
    Jens Glaser
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    *[email protected]
    More by Jens Glaser
  • Ada Sedova
    Ada Sedova
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    More by Ada Sedova
  • Stephanie Galanie
    Stephanie Galanie
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    Protein Engineering, Merck, 126 East Lincoln Avenue, RY800-C303, Rahway, New Jersey 07065, United States
  • Daniel W. Kneller
    Daniel W. Kneller
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    New England Biolabs, 240 County Road, Ipswich, Massachusetts 01938, United States
  • Russell B. Davidson
    Russell B. Davidson
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Elvis Maradzike
    Elvis Maradzike
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Sara Del Galdo
    Sara Del Galdo
    Department of Physical and Chemical Sciences, University of L’Aquila, I-67010 L’Aquila, Italy
  • Audrey Labbé
    Audrey Labbé
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Darren J. Hsu
    Darren J. Hsu
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Rupesh Agarwal
    Rupesh Agarwal
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Dmytro Bykov
    Dmytro Bykov
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    More by Dmytro Bykov
  • Arnold Tharrington
    Arnold Tharrington
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Jerry M. Parks
    Jerry M. Parks
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Dayle M. A. Smith
    Dayle M. A. Smith
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Isabella Daidone
    Isabella Daidone
    Department of Physical and Chemical Sciences, University of L’Aquila, I-67010 L’Aquila, Italy
  • Leighton Coates
    Leighton Coates
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • Andrey Kovalevsky
    Andrey Kovalevsky
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
  • , and 
  • Jeremy C. Smith*
    Jeremy C. Smith
    Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37830, United States
    *[email protected]
Cite this: ACS Pharmacol. Transl. Sci. 2022, 5, 4, 255–265
Publication Date (Web):April 4, 2022
https://doi.org/10.1021/acsptsci.2c00026
Copyright © 2022 American Chemical Society

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    Supporting Info (2)»

    Abstract

    Abstract Image

    Inhibition of the SARS-CoV-2 main protease (Mpro) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of Mpro. Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC50 values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein–inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for Mpro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library.

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    Supporting Information

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    The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsptsci.2c00026.

    • Figure S1, validation of the enzymatic assay; Table S1, crystallographic data collection and refinement statistics for room-temperature structures of Mpro in complex with compounds 12, 19, and 21; and Table S2, list of Mpro crystal structures (PDB IDs) used for the hydration analysis (PDF)

    • Characterization of compounds, including purity, molecular formula (SMILES) strings, and activities (XLSX)

    Accession Codes

    The PDB accession codes are 7S3K for Mpro:compound 12, 7S4B for Mpro:compound 19, and 7S3S for Mpro:compound 21.

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    Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html.

    Cited By

    This article is cited by 6 publications.

    1. Amgad M. Rabie, Marwa A. Abdel-Dayem, Mohnad Abdalla. Promising Experimental Anti-SARS-CoV-2 Agent “SLL-0197800”: The Prospective Universal Inhibitory Properties against the Coming Versions of the Coronavirus. ACS Omega 2023, 8 (39) , 35538-35554. https://doi.org/10.1021/acsomega.2c08073
    2. Wafa A. Eltayb, Mohnad Abdalla, Amgad M. Rabie. Novel Investigational Anti-SARS-CoV-2 Agent Ensitrelvir “S-217622”: A Very Promising Potential Universal Broad-Spectrum Antiviral at the Therapeutic Frontline of Coronavirus Species. ACS Omega 2023, 8 (6) , 5234-5246. https://doi.org/10.1021/acsomega.2c03881
    3. Mehdi Valipour. Different Aspects of Emetine’s Capabilities as a Highly Potent SARS-CoV-2 Inhibitor against COVID-19. ACS Pharmacology & Translational Science 2022, 5 (6) , 387-399. https://doi.org/10.1021/acsptsci.2c00045
    4. Ya.O. Ivanova, A.I. Voronina, V.S. Skvortsov. The prediction of SARS-CoV-2 main protease inhibition with filtering by position of ligand. Biomeditsinskaya Khimiya 2022, 68 (6) , 444-458. https://doi.org/10.18097/pbmc20226806444
    5. Qing Hu, Yuan Xiong, Guang‐Hao Zhu, Ya‐Ni Zhang, Yi‐Wen Zhang, Ping Huang, Guang‐Bo Ge. The SARS‐CoV‐2 main protease (M pro ): Structure, function, and emerging therapies for COVID‐19. MedComm 2022, 3 (3) https://doi.org/10.1002/mco2.151
    6. Yves L Janin. On drug discovery against infectious diseases and academic medicinal chemistry contributions. Beilstein Journal of Organic Chemistry 2022, 18 , 1355-1378. https://doi.org/10.3762/bjoc.18.141

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