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

Abstract：

: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.

journal_name

Bioorg Med Chem Lett

journal_title

Bioorganic & medicinal chemistry letters

authors

Weng Z,Xu G,Chen D,Yang Y,Song G,Shen W,Zhang S,Wang L,Yang W,Zuo Z

doi

10.1016/j.bmcl.2019.126823

subject

Has Abstract

pub_date

2020-01-15 00:00:00

pages

126823

issue

2

eissn

0960-894X

issn

1464-3405

pii

S0960-894X(19)30792-9

journal_volume

30

pub_type

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