In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing

doi:10.1021/acs.jcim.0c00171

	In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing
	Zhao, Wenfeng 2,3,4; Xiong, Muya 4,5; Yuan, Xiaojing 4,5; Li, Minjun 1; Sun, Hongbin 2,3; Xu, Yechun 4,5
刊名	JOURNAL OF CHEMICAL INFORMATION AND MODELING
	2020-06-22
卷号	60 期号:6 页码:3265-3276
ISSN号	1549-9596
DOI	10.1021/acs.jcim.0c00171
通讯作者	Sun, Hongbin(hongbinsun@cpu.edu.cn) ; Xu, Yechun(ycxu@simm.ac.cn)
英文摘要	Cyclic GMP-AMP synthase (cGAS) has been recently uncovered to be a promising therapeutic target for immune-associated diseases. Until now, only a few inhibitors have been identified through high-throughput screening campaigns. Here, we reported the discovery of novel inhibitors for the catalytic domain of human cGAS (h-cGAS(CD)) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGAS(CD) in complex with PF-06928215, a known inhibitor of h-cGAS, followed by molecular dynamics simulations on this complex structure. Four fragment hits were identified by the virtual screening together with a thermal shift assay. The crystal structures of these four compounds in complex with h-cGAS(CD) were subsequently determined, and the binding modes of the compounds were similar to those predicted by molecular docking, supporting the reliability of the docking model. In addition, an enzyme activity assay identified compound 18 (IC50 = 29.88 +/- 3.20 mu M) from the compounds predicted by the virtual screening. A similarity search of compound 18 followed by a second virtual screening led to the discovery of compounds S2 (IC50 = 13.1 +/- 0.09 mu M) and S3 (IC50 = 4.9 +/- 0.26 mu M) as h-cGAS inhibitors with improved potency. Therefore, the present study not only provides the validated hit compounds for further development of h-cGAS inhibitors but also demonstrates a cross-validation study of virtual screening, in vitro experimental assays, and crystal structure determination.
资助项目	National Key R&D Program of China[2017YFB0202604] ; National Natural Science Foundation of China[21877122]
WOS关键词	AICARDI-GOUTIERES-SYNDROME ; DNA SENSOR ; CGAS ; PROTEIN ; 2ND-MESSENGER ; MODEL ; DINUCLEOTIDE ; INFLAMMATION ; PARAMETERS ; MUTATIONS
WOS研究方向	Pharmacology & Pharmacy ; Chemistry ; Computer Science
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000543717300054
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291980]
专题	中国科学院上海药物研究所
通讯作者	Sun, Hongbin; Xu, Yechun
作者单位	1.Chinese Acad Sci, Shanghai Adv Res Inst, Shanghai Synchrotron Radiat Facil, Shanghai 201210, Peoples R China 2.China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, Nanjing 210009, Peoples R China 3.China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式 GB/T 7714	Zhao, Wenfeng,Xiong, Muya,Yuan, Xiaojing,et al. In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing[J]. JOURNAL OF CHEMICAL INFORMATION AND MODELING,2020,60(6):3265-3276.
APA	Zhao, Wenfeng,Xiong, Muya,Yuan, Xiaojing,Li, Minjun,Sun, Hongbin,&Xu, Yechun.(2020).In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing.JOURNAL OF CHEMICAL INFORMATION AND MODELING,60(6),3265-3276.
MLA	Zhao, Wenfeng,et al."In Silico Screening-Based Discovery of Novel Inhibitors of Human Cyclic GMP-AMP Synthase: A Cross-Validation Study of Molecular Docking and Experimental Testing".JOURNAL OF CHEMICAL INFORMATION AND MODELING 60.6(2020):3265-3276.