Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Elissa A. Fink; Conner Bardine; Stefan Gahbauer; Isha Singh; Tyler C. Detomasi; Kris White; Shuo Gu; Xiaobo Wan; Jun Chen; Beatrice Ary; Isabella Glenn; Joseph O'Connell; Henry O'Donnell; Pavla Fajtová; Jiankun Lyu; Seth Vigneron; Nicholas J. Young; Ivan S. Kondratov; Arghavan Alisoltani; Lacy M. Simons; Ramon Lorenzo-Redondo; Egon A. Ozer; Judd F. Hultquist; Anthony J. O'Donoghue; Yurii S. Moroz; Jack Taunton; Adam R. Renslo; John J. Irwin; Adolfo García-Sastre; Brian K. Shoichet; Charles S. Craik

doi:10.1002/pro.4712

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Elissa A. Fink, Conner Bardine, Stefan Gahbauer, Isha Singh, Tyler C. Detomasi, Kris White, Shuo Gu, Xiaobo Wan, Jun Chen, Beatrice Ary, Isabella Glenn, Joseph O'Connell, Henry O'Donnell, Pavla Fajtová, Jiankun Lyu, Seth Vigneron, Nicholas J. Young, Ivan S. Kondratov, Arghavan Alisoltani, Lacy M. SimonsRamon Lorenzo-Redondo, Egon A. Ozer, Judd F. Hultquist, Anthony J. O'Donoghue, Yurii S. Moroz, Jack Taunton, Adam R. Renslo, John J. Irwin, Adolfo García-Sastre, Brian K. Shoichet^*, Charles S. Craik^*

^*Corresponding author for this work

Medicine, Infectious Diseases Division

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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 (M^Pro), 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 M^Pro inhibitors for SARS-CoV-2, the modest success rate also reveals weaknesses in our approach for challenging targets like M^Pro versus other targets where it has been more successful, and versus other structure-based techniques against M^Pro itself.

Original language	English (US)
Article number	e4712
Journal	Protein Science
Volume	32
Issue number	8
DOIs	https://doi.org/10.1002/pro.4712
State	Published - Aug 2023

Keywords

SARS-COV-2
discoverydockinganti-viral
major protease
structure-based inhibitor

ASJC Scopus subject areas

Molecular Biology
Biochemistry

Access to Document

10.1002/pro.4712

Cite this

Fink, E. A., Bardine, C., Gahbauer, S., Singh, I., Detomasi, T. C., White, K., Gu, S., Wan, X., Chen, J., Ary, B., Glenn, I., O'Connell, J., O'Donnell, H., Fajtová, P., Lyu, J., Vigneron, S., Young, N. J., Kondratov, I. S., Alisoltani, A., ... Craik, C. S. (2023). Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors. Protein Science, 32(8), Article e4712. https://doi.org/10.1002/pro.4712

@article{13ce132597134eff8f15694bc316142b,

title = "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.",

keywords = "SARS-COV-2, discoverydockinganti-viral, major protease, structure-based inhibitor",

author = "Fink, {Elissa A.} and Conner Bardine and Stefan Gahbauer and Isha Singh and Detomasi, {Tyler C.} and Kris White and Shuo Gu and Xiaobo Wan and Jun Chen and Beatrice Ary and Isabella Glenn and Joseph O'Connell and Henry O'Donnell and Pavla Fajtov{\'a} and Jiankun Lyu and Seth Vigneron and Young, {Nicholas J.} and Kondratov, {Ivan S.} and Arghavan Alisoltani and Simons, {Lacy M.} and Ramon Lorenzo-Redondo and Ozer, {Egon A.} and Hultquist, {Judd F.} and O'Donoghue, {Anthony J.} and Moroz, {Yurii S.} and Jack Taunton and Renslo, {Adam R.} and Irwin, {John J.} and Adolfo Garc{\'i}a-Sastre and Shoichet, {Brian K.} and Craik, {Charles S.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Protein Society.",

year = "2023",

month = aug,

doi = "10.1002/pro.4712",

language = "English (US)",

volume = "32",

journal = "Protein Science",

issn = "0961-8368",

publisher = "Wiley-Blackwell",

number = "8",

}

Fink, EA, Bardine, C, Gahbauer, S, Singh, I, Detomasi, TC, White, K, Gu, S, Wan, X, Chen, J, Ary, B, Glenn, I, O'Connell, J, O'Donnell, H, Fajtová, P, Lyu, J, Vigneron, S, Young, NJ, Kondratov, IS, Alisoltani, A, Simons, LM, Lorenzo-Redondo, R , Ozer, EA , Hultquist, JF, O'Donoghue, AJ, Moroz, YS, Taunton, J, Renslo, AR, Irwin, JJ, García-Sastre, A, Shoichet, BK & Craik, CS 2023, 'Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors', Protein Science, vol. 32, no. 8, e4712. https://doi.org/10.1002/pro.4712

TY - JOUR

T1 - Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

AU - Fink, Elissa A.

AU - Bardine, Conner

AU - Gahbauer, Stefan

AU - Singh, Isha

AU - Detomasi, Tyler C.

AU - White, Kris

AU - Gu, Shuo

AU - Wan, Xiaobo

AU - Chen, Jun

AU - Ary, Beatrice

AU - Glenn, Isabella

AU - O'Connell, Joseph

AU - O'Donnell, Henry

AU - Fajtová, Pavla

AU - Lyu, Jiankun

AU - Vigneron, Seth

AU - Young, Nicholas J.

AU - Kondratov, Ivan S.

AU - Alisoltani, Arghavan

AU - Simons, Lacy M.

AU - Lorenzo-Redondo, Ramon

AU - Ozer, Egon A.

AU - Hultquist, Judd F.

AU - O'Donoghue, Anthony J.

AU - Moroz, Yurii S.

AU - Taunton, Jack

AU - Renslo, Adam R.

AU - Irwin, John J.

AU - García-Sastre, Adolfo

AU - Shoichet, Brian K.

AU - Craik, Charles S.

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - SARS-COV-2

KW - discoverydockinganti-viral

KW - major protease

KW - structure-based inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85165905447&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85165905447&partnerID=8YFLogxK

U2 - 10.1002/pro.4712

DO - 10.1002/pro.4712

M3 - Article

C2 - 37354015

AN - SCOPUS:85165905447

SN - 0961-8368

VL - 32

JO - Protein Science

JF - Protein Science

IS - 8

M1 - e4712

ER -

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Cite this

Large library docking for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Virtual screening for novel SARS-CoV-2 main protease non-covalent and covalent inhibitors

Cite this