2. Academic Validation
  3. Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease

Structural, Electronic, and Electrostatic Determinants for Inhibitor Binding to Subsites S1 and S2 in SARS-CoV-2 Main Protease

  • J Med Chem. 2021 Dec 9;64(23):17366-17383. doi: 10.1021/acs.jmedchem.1c01475.
Daniel W Kneller 1 2,  Hui Li 2 3,  Stephanie Galanie 2 4,  Gwyndalyn Phillips 1 2,  Audrey Labbé 2 4,  Kevin L Weiss 1 2,  Qiu Zhang 1 2,  Mark A Arnould 2 3,  Austin Clyde 2 5 6,  Heng Ma 2 5,  Arvind Ramanathan 2 5 7,  Colleen B Jonsson 8,  Martha S Head 2 9,  Leighton Coates 2 10,  John M Louis 11,  Peter V Bonnesen 2 3,  Andrey Kovalevsky 1 2
Affiliations

Affiliations

  • 1 Neutron Scattering Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
  • 2 National Virtual Biotechnology Laboratory, US Department of Energy, Washington, District of Columbia 20585, United States.
  • 3 Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
  • 4 Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
  • 5 Data Science and Learning Division, Argonne National Laboratory, Lemont, Illinois 60439, United States.
  • 6 Department of Computer Science, University of Chicago, Chicago, Illinois 60615, United States.
  • 7 Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois 60615, United States.
  • 8 Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, Tennessee 38163, United States.
  • 9 Joint Institute for Biological Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
  • 10 Second Target Station, Oak Ridge National Laboratory, Oak Ridge, Tennessee 37831, United States.
  • 11 Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, Maryland 20892-0520, United States.
PMID: 34705466 DOI: 10.1021/acs.jmedchem.1c01475
Abstract

Creating small-molecule antivirals specific for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins is crucial to battle coronavirus disease 2019 (COVID-19). SARS-CoV-2 main protease (Mpro) is an established drug target for the design of Protease Inhibitors. We performed a structure-activity relationship (SAR) study of noncovalent compounds that bind in the enzyme's substrate-binding subsites S1 and S2, revealing structural, electronic, and electrostatic determinants of these sites. The study was guided by the X-ray/neutron structure of Mpro complexed with Mcule-5948770040 (compound 1), in which protonation states were directly visualized. Virtual reality-assisted structure analysis and small-molecule building were employed to generate analogues of 1. In vitro Enzyme inhibition assays and room-temperature X-ray structures demonstrated the effect of chemical modifications on Mpro inhibition, showing that (1) maintaining correct geometry of an inhibitor's P1 group is essential to preserve the hydrogen bond with the protonated His163; (2) a positively charged linker is preferred; and (3) subsite S2 prefers nonbulky modestly electronegative groups.

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