Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening.

Zhiying Weng, Guowei Xu, Dingyuan Chen, Yaqing Yang, Gao Song, Wen Shen, Shuqun Zhang, LiangLiang Wang, Weimin Yang, Zhili Zuo

Bioorganic & medicinal chemistry letters 2020 Jan 15

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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 an in-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 EC50 value 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. Copyright © 2019 Elsevier Ltd. All rights reserved.

Citation

Zhiying Weng, Guowei Xu, Dingyuan Chen, Yaqing Yang, Gao Song, Wen Shen, Shuqun Zhang, LiangLiang Wang, Weimin Yang, Zhili Zuo. Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening. Bioorganic & medicinal chemistry letters. 2020 Jan 15;30(2):126823