Virtual screening based on pharmacophoric features of known calpain inhibitors to identify potent inhibitors of calpain

Abstract

Calpain, a member of the group of cysteine protease enzymes, has been recognized as a promising drug target for several diseases, including cataract. In the present study, an attempt was made to identify potential inhibitors of calpain by employing a pharmacophore-based virtual screening and docking approach. A knowledge-based 3D pharmacophore model was generated, based on the features of established calpain inhibitors SJA6017, MDL28170, E64D, SNJ 1715, calpastatin and CHEMBL 1921830, using the PHASE module of Schrodinger Suite. The best pharmacophore model (AAADH) derived consisted of five features, namely three hydrogen bond acceptors, one hydrogen bond donor and one hydrophobic region. This common pharmacophore hypothesis was then used to perform virtual screening against a binding database, with due consideration to the Lipinski ‘rule of five’ and absorption, distribution, metabolism, excretion properties were calculated using the Qikprop module, so as to obtain a pool of lead molecules. The short-listed lead molecules were then subjected to docking analysis with that of the mutated calpain 1 (1KXR) to reduce the false positive and false negative results against the target receptor. Interaction data and its corresponding interaction energy, along with binding energy calculated for the hit ligand (650709) and mutated receptor (1KXR) complex, suggest that compound 650709 has a more effective inhibitory potential than that of the other established calpain inhibitors.