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.