2. Academic Validation
  3. 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

  • Bioorg Med Chem Lett. 2020 Jan 15;30(2):126823. doi: 10.1016/j.bmcl.2019.126823.
Zhiying Weng 1,  Guowei Xu 2,  Dingyuan Chen 2,  Yaqing Yang 1,  Gao Song 1,  Wen Shen 3,  Shuqun Zhang 2,  LiangLiang Wang 2,  Weimin Yang 4,  Zhili Zuo 5
Affiliations

Affiliations

  • 1 School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, Yunnan, China.
  • 2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China.
  • 3 Department of Respiratory Medicine, The Second Affiliated Hospital of Kunming Medical University, Kunming 650031, Yunnan, China.
  • 4 School of Pharmaceutical Science & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming 650500, Yunnan, China. Electronic address: ywmbessie@yeah.net.
  • 5 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, Yunnan, China. Electronic address: zuozhili@mail.kib.ac.cn.
PMID: 31776060 DOI: 10.1016/j.bmcl.2019.126823
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.

Keywords

Adenylyl cyclases; Biological evaluation; Consensus scoring; Homology modeling; Molecular dynamics simulation; Virtual screening.

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