6LRL

Human cGAS catalytic domain bound with compound s2

6LRL の概要

• エントリーDOI: 10.2210/pdb6lrl/pdb
• 分子名称: Cyclic GMP-AMP synthase, ZINC ION, 3-[[5-(1,2,4-triazol-4-yl)-4H-1,2,4-triazol-3-yl]carbonylamino]benzoic acid (3 entities in total)
• 機能のキーワード: cgas, inhibitor, complex structure, dna binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 85948.60

構造登録者

Zhao, W.F.,Xiong, M.Y.,Yuan, X.J.,Sun, H.B.,Xu, Y.C. (登録日: 2020-01-16, 公開日: 2020-06-24, 最終更新日: 2023-11-29)

主引用文献

Zhao, W.,Xiong, M.,Yuan, X.,Li, M.,Sun, H.,Xu, Y.
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.Chem.Inf.Model., 60:3265-3276, 2020

PubMed Abstract: 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) by virtual screening for the first time. To generate a reliable docking mode, we first obtained a high-resolution crystal structure of h-cGAS 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 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 (IC = 29.88 ± 3.20 μM) from the compounds predicted by the virtual screening. A similarity search of compound followed by a second virtual screening led to the discovery of compounds (IC = 13.1 ± 0.09 μM) and (IC = 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.

PubMed: 32459092
DOI: 10.1021/acs.jcim.0c00171

実験手法

X-RAY DIFFRACTION (2.655 Å)