Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening
Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening
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通过基于对接的虚拟筛选发现有效且选择性的 8 型腺苷酸环化酶激动剂
DOI：
10.1016/j.bmcl.2019.126823
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发表时间：
2020
影响因子：
2.7
通讯作者：
Zhili Zuo
中科院分区：
文献类型：
--
作者：
Zhiying Weng;Guowei Xu;Dingyuan Chen;Yaqing Yang;Wen Shen;Shuqun Zhang;Liang-Liang Wang;Weimin Yang;Zhili Zuo
腺苷环化酶(ACS)负责催化三磷酸腺苷(ATP)转化为第二信使环磷酸腺苷(CAMP)，在细胞信号转导中起着关键作用。在本研究中，采用基于对接的虚拟筛选、同源建模和体外实验相结合的方法和基于细胞的生物实验相结合的方法，发现了一类新的有效和选择性的异构型腺苷酸环化酶8(AC8)激动剂。使用计算机辅助的虚拟筛选来确定14个虚拟簇化合物作为潜在的命中，并进一步进行严格的生物测定。新的HIT化合物VHC-7(乙基3-(2，4-dichlorobenzyl)-2-oxoindoline-3-carboxylate))被鉴定为一种高效的选择性AC8激动剂，EC50值为0.1052±0.038µM。值得注意的是，本文报道的分子可以进一步探索，以发现更多具有更好药代动力学性质的HIT化合物，并有望成为AC8的新型HIT激动剂，用于治疗各种中枢神经系统疾病及其相关疾病。
Adenylyl cyclases (ACs), which are responsible for catalyzing the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP), play a critical role in cell signal transduction. In this study, a combined approach involving docking-based virtual screening, with the combination of homology modeling followed by anin-vitro, and cell-based biological assay have been performed for discovering a class of novel potent and selective isoform adenylyl cyclase type 8 (AC8) agonist. The computer-aided virtual screening was used to identify fourteen virtual cluster compounds as potential hits which were further subjected to rigorous bioassays. A novel hit compound VHC-7 (ethyl 3-(2,4-dichlorobenzyl)-2-oxoindoline-3-carboxylate) was identified as a highly potent selective AC8 agonist with EC50value of 0.1052 ± 0.038 µM. Remarkably, the molecule herein reported can be explored further to discover greater number of hit compounds with better pharmacokinetic properties as well as to serve as a promising novel hit agonist of AC8 for the treatment of various central nervous system disorders and its associated diseases.