Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations

doi:10.1021/acs.jcim.4c01594

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	Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations
	Xiong, Muya 1,2; Nie, Tianqing 3,4; Li, Zhewen 2,5; Hu, Meiyi 2; Su, Haixia 2,5; Hu, Hangchen 2,5; Xu, Yechun1,2,5 ; Shao, Qiang2,5
	2024-11-28
发表期刊	JOURNAL OF CHEMICAL INFORMATION AND MODELING (IF:3.804[JCR-2017],4.111[5-Year])
ISSN	1549-9596
卷号	64 期号:24 页码:9501-9516
摘要	3-Chymotrypsin-like protease (3CLpro) is a prominent target against pathogenic coronaviruses. Expert knowledge of the cysteine-targeted covalent reaction mechanism is crucial to predict the inhibitory potency of approved inhibitors against 3CLpros of SARS-CoV-2 variants and perform structure-based drug design against newly emerging coronaviruses. We carried out an extensive array of classical and hybrid QM/MM molecular dynamics simulations to explore covalent inhibition mechanisms of five well-characterized inhibitors toward SARS-CoV-2 3CLpro and its mutants. The calculated binding affinity and reactivity of the inhibitors are highly consistent with experimental data, and the predicted inhibitory potency of the inhibitors against 3CLpro with L167F, E166V, or T21I/E166V mutant is in full agreement with IC50s determined by the accompanying enzymatic assays. The explored mechanisms unveil the impact of residue mutagenesis on structural dynamics that communicates to change not only noncovalent binding strength but also covalent reaction free energy. Such a change is inhibitor dependent, corresponding to varied levels of drug resistance of these 3CLpro mutants against nirmatrelvir and simnotrelvir and no resistance to the 11a compound. These results together suggest that the present simulations with a suitable protocol can efficiently evaluate the reactivity and potency of covalent inhibitors along with the elucidated molecular mechanisms of covalent inhibition.
WOS关键词	SCC-DFTB METHOD ; MOLECULAR-DYNAMICS ; 3CL PROTEASES ; CYSTEINE ; IMPLEMENTATION ; MECHANISM ; DISCOVERY
DOI	10.1021/acs.jcim.4c01594
收录类别	SCI
资助项目	National Natural Science Foundation of China[32071248] ; National Natural Science Foundation of China[22277130] ; National Natural Science Foundation of China[22307133] ; National Natural Science Foundation of China[32301050] ; National Natural Science Foundation of China
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
WOS类目	Chemistry, Medicinal ; Chemistry, Multidisciplinary ; Computer Science, Information Systems ; Computer Science, Interdisciplinary Applications
WOS记录号	WOS:001366395100001
出版者	AMER CHEMICAL SOC
引用统计	被引频次：2[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.183/handle/2S10ELR8/314802
专题	新药研究国家重点实验室
通讯作者	Xu, Yechun; Shao, Qiang
作者单位	1.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Lingang Lab, Shanghai 200031, Peoples R China 4.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
第一作者单位	新药研究国家重点实验室
通讯作者单位	新药研究国家重点实验室
推荐引用方式 GB/T 7714	Xiong, Muya,Nie, Tianqing,Li, Zhewen,et al. Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2024,64(24):9501-9516.
APA	Xiong, Muya.,Nie, Tianqing.,Li, Zhewen.,Hu, Meiyi.,Su, Haixia.,...&Shao, Qiang.(2024).Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations.JOURNAL OF CHEMICAL INFORMATION AND MODELING,64(24),9501-9516.
MLA	Xiong, Muya,et al."Potency Prediction of Covalent Inhibitors against SARS-CoV-2 3CL-like Protease and Multiple Mutants by Multiscale Simulations".JOURNAL OF CHEMICAL INFORMATION AND MODELING 64.24(2024):9501-9516.