Design and Optimization of Novel Competitive, Non-peptidic, SARS-CoV-2 Mpro Inhibitors

被引：6

作者：

Jacobs, Leon ^{[1
]}

van der Westhuyzen, Aletta ^{[1
]}

Pribut, Nicole ^{[1
]}

Dentmon, Zackery W. ^{[1
,2
]}

Cui, Dan ^{[3
]}

D'Erasmo, Michael P. ^{[1
,4
]}

Bartsch, Perry W. ^{[1
]}

Liu, Ken ^{[1
]}

Cox, Robert M. ^{[5
]}

Greenlund, Sujay F. ^{[5
]}

Plemper, Richard K. ^{[5
]}

Mitchell, Deborah ^{[6
]}

Marlow, Joshua ^{[6
]}

Andrews, Meghan K. ^{[6
]}

Krueger, Rebecca E. ^{[6
]}

Sticher, Zachary M. ^{[6
]}

Kolykhalov, Alexander A. ^{[6
]}

Natchus, Michael G. ^{[6
]}

Zhou, Bin ^{[3
]}

Pelly, Stephen C. ^{[1
]}

Liotta, Dennis C. ^{[1
]}

机构：

[1] Emory Univ, Dept Chem, Atlanta, GA 30322 USA

[2] Avicenna Biosci Inc, Durham, NC 27701 USA

[3] Ctr Dis Control & Prevent, COVID 19 Emergency Response, Atlanta, GA 30329 USA

[4] Charles River Labs, Worcester, MA 01605 USA

[5] Georgia State Univ, Inst Biomed Sci, Ctr Translat Antiviral Res, Atlanta, GA 30303 USA

[6] Emory Univ, Emory Inst Drug Dev, Atlanta, GA 30322 USA

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2023年

关键词：

SARS-CoV-2; COVID-19; main protease; FEP plus; MAIN PROTEASE;

D O I：

10.1021/acsmedchemlett.3c00335

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The SARS-CoV-2 main protease (M-pro) has been proven to be a highly effective target for therapeutic intervention, yet only one drug currently holds FDA approval status for this target. We were inspired by a series of publications emanating from the Jorgensen and Anderson groups describing the design of potent, non-peptidic, competitive SARS-CoV-2 M-pro inhibitors, and we saw an opportunity to make several design modifications to improve the overall pharmacokinetic profile of these compounds without losing potency. To this end, we created a focused virtual library using reaction-based enumeration tools in the Schro''dinger suite. These compounds were docked into the M(pro )active site and subsequently prioritized for synthesis based upon relative binding affinity values calculated by FEP+. Fourteen compounds were selected, synthesized, and evaluated both biochemically and in cell culture. Several of the synthesized compounds proved to be potent, competitive Mpro inhibitors with improved metabolic stability profiles.

引用

页码：1434 / 1440

页数：7

共 18 条

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