Large library docking for novel SARS‐CoV‐2 main protease non‐covalent and covalent inhibitors
Abstract
Antiviral therapeutics to treat SARS‐CoV‐2 are needed to diminish the morbidity of the ongoing COVID‐19 pandemic. A well‐precedented drug target is the main viral protease (MPro), which is targeted by an approved drug and by several investigational drugs. Emerging viral resistance has made new inhibitor chemotypes more pressing. Adopting a structure‐based approach, we docked 1.2 billion non‐covalent lead‐like molecules and a new library of 6.5 million electrophiles against the enzyme structure. From these, 29 non‐covalent and 11 covalent inhibitors were identified in 37 series, the most potent having an IC50 of 29 and 20 μM, respectively. Several series were optimized, resulting in low micromolar inhibitors. Subsequent crystallography confirmed the docking predicted binding modes and may template further optimization. While the new chemotypes may aid further optimization of MPro inhibitors for SARS‐CoV‐2, the modest success rate also reveals weaknesses in our approach for challenging targets like MPro versus other targets where it has been more successful, and versus other structure‐based techniques against MPro itself.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 24, 2023
- Source ID
- 10.1002/pro.4712
Entities
People
- Adam R Renslo
- Adolfo García‐sastre
- Anthony J. O'Donoghue
- Arghavan Alisoltani
- Beatrice Ary
- Brian K. Shoichet
- Charles S Craik
- Conner Bardine
- Egon A Ozer
- Elissa A. Fink
- Henry O’Donnell
- Isabella Glenn
- Isha Singh
- Ivan S. Kondratov
- Jack Taunton
- Jiankun Lyu
- John J Irwin
- Joseph W. O'Connell
- Judd F. Hultquist
- Jun Chen
- Kris M White
- Lacy M. Simons
- Nicholas J. Young
- Pavla Fajtová
- Ramon Lorenzo‐redondo
- Seth Vigneron
- Shuo Gu
- Stefan Gahbauer
- Tyler C. Detomasi
- Xiaobo Wan
- Yurii S. Moroz
Organizations
- Defense Advanced Research Projects Agency
- Enamine Ltd
- Icahn School of Medicine at Mount Sinai
- National Institute of Allergy and Infectious Diseases
- National Institutes of Health
- Northwestern University
- United States Department of Defense
- University of California, San Diego
- University of California, San Francisco