Discovery of novel inhibitors of SARS-CoV-2 main protease

Lei Zheng; Yanmei Chen; Jingxiao Bao; Liping He; Suzhen Dong; Yifei Qi; John Z.H. Zhang

doi:10.1080/07391102.2021.1972041

Discovery of novel inhibitors of SARS-CoV-2 main protease

Lei Zheng, Yanmei Chen, Jingxiao Bao, Liping He, Suzhen Dong, Yifei Qi, John Z.H. Zhang

Chemistry

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

Abstract

Corona Virus Disease 2019 (COVID-19), referred to as ‘New Coronary Pneumonia’, is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. M^pro is one of the main targets for treating COVID-19. The current research on M^pro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit M^pro. In this research, we used computational free energy calculation to screen a compound library against M^pro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC₅₀ of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and M^pro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma.

Original language	English (US)
Pages (from-to)	12526-12534
Number of pages	9
Journal	Journal of Biomolecular Structure and Dynamics
Volume	40
Issue number	23
DOIs	https://doi.org/10.1080/07391102.2021.1972041
State	Published - 2022

Keywords

COVID-19
inhibitory activity
main protease
virtual screening

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1080/07391102.2021.1972041

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title = "Discovery of novel inhibitors of SARS-CoV-2 main protease",

abstract = "Corona Virus Disease 2019 (COVID-19), referred to as {\textquoteleft}New Coronary Pneumonia{\textquoteright}, is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma.",

keywords = "COVID-19, inhibitory activity, main protease, virtual screening",

author = "Lei Zheng and Yanmei Chen and Jingxiao Bao and Liping He and Suzhen Dong and Yifei Qi and Zhang, {John Z.H.}",

note = "Funding Information: This work was supported by the National Natural Science Foundation of China (Grant 91753103, 31700646, 21933010), and the Natural Science Foundation of Shanghai (Grant 19ZR1473600). We thank NYU Shanghai and the ECNU Multifunctional Platform for Innovation (001) for providing us computer time. Publisher Copyright: {\textcopyright} 2021 Informa UK Limited, trading as Taylor & Francis Group.",

year = "2022",

doi = "10.1080/07391102.2021.1972041",

language = "English (US)",

volume = "40",

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T1 - Discovery of novel inhibitors of SARS-CoV-2 main protease

AU - Zheng, Lei

AU - Chen, Yanmei

AU - Bao, Jingxiao

AU - He, Liping

AU - Dong, Suzhen

AU - Qi, Yifei

AU - Zhang, John Z.H.

N1 - Funding Information: This work was supported by the National Natural Science Foundation of China (Grant 91753103, 31700646, 21933010), and the Natural Science Foundation of Shanghai (Grant 19ZR1473600). We thank NYU Shanghai and the ECNU Multifunctional Platform for Innovation (001) for providing us computer time. Publisher Copyright: © 2021 Informa UK Limited, trading as Taylor & Francis Group.

PY - 2022

Y1 - 2022

N2 - Corona Virus Disease 2019 (COVID-19), referred to as ‘New Coronary Pneumonia’, is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma.

AB - Corona Virus Disease 2019 (COVID-19), referred to as ‘New Coronary Pneumonia’, is a type of acute infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. Mpro is one of the main targets for treating COVID-19. The current research on Mpro mainly focuses on the repurposing of old drugs, and there are only a few novel ligands that inhibit Mpro. In this research, we used computational free energy calculation to screen a compound library against Mpro, and discovered four novel compounds with the two best compounds (AG-690/13507628 and AG-690/13507724) having experimental measured IC50 of just under 3 μM and low cell toxicity. Detailed decomposition of the interactions between the inhibitors and Mpro reveals key interacting residues and interactions that determine the activity. The results from this study should provide a basis for further development of anti-SARS-CoV-2 drugs. Communicated by Ramaswamy H. Sarma.

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Discovery of novel inhibitors of SARS-CoV-2 main protease

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