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
  • 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: [email protected].
  • 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: [email protected].
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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