Pancreatic cholesterol esterase (CEase) is a serine hydrolase involved in the 
hydrolysis of variety of lipids and transport of free cholesterol. In this 
study, pharmacophore hypotheses based on known inhibitors were generated using 
common feature pharmacophore generation protocol available in Discovery Studio 
program. The best pharmacophore model containing two hydrogen bond acceptor and 
three hydrophobic features was selected and validated. It was further used in 
screening three diverse chemical databases. Hit compounds were subjected to 
drug-likeness and molecular docking studies. Four hits, namely SEW00846, 
NCI0040784, GK03167, and CD10645, were selected based on the GOLD fitness score 
and interaction with active site amino acids. All hit compounds were further 
optimized to improve their binding in the active site. The optimized compounds 
were found to have improved binding at the active site. Strongly binding 
optimized hits at the active site can act as virtual leads in potent CEase 
inhibitor designing.