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

虚拟筛选 生物信息学 对接(动物) 计算生物学 高通量筛选 药物发现 IC50型 化学 ATP合酶 结构相似性 小分子 广告 体外 生物化学 生物 医学 基因 护理部
作者
Wenfeng Zhao,Muya Xiong,Xiaojing Yuan,Minjun Li,Hongbin Sun,Yechun Xu
出处
期刊:Journal of Chemical Information and Modeling [American Chemical Society]
卷期号:60 (6): 3265-3276 被引量:49
标识
DOI:10.1021/acs.jcim.0c00171
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-cGASCD) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGASCD 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-cGASCD 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 μM) 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 μM) and S3 (IC50 = 4.9 ± 0.26 μM) 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.
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