Virtual Screening of Cathepsin K Inhibitors Using Docking and Pharmacophore Models

Cathepsin K is a lysosomal cysteine protease that is highly and selectively expressed in osteo-clasts, the cells which degrade bone during the continuous cycle of bone degradation and forma-tion. Inhibition of cathepsin K represents a potential therapeutic approach for diseases char-acterized by excessive bone resorption such as osteoporosis. In order to elucidate the essential structural features for cathepsin K, a three-dimensional pharmacophore hypotheses were built on the basis of a set of known cathepsin K inhibitors selected from the literature using CATALYST program. Several methods are used in validation of pharmacophore hypothesis were presented, and the fourth hypothesis (Hypo4) was considered to be the best pharmacophore hypothesis which has a correlation coefficient of 0.944 with training set and has high prediction of activity for a set of 30 test molecules with correlation of 0.909. The model (Hypo4) was then employed as 3D search query to screen the Maybridge database containing 59 000 com-pounds, to discover novel and highly potent ligands. For analyzing intermolecular interactions between protein and ligand, all the molecules were docked using Glide software. The result showed that the type and spatial location of che-mical features encoded in the pharmacophore are in full agreement with the enzyme inhibitor interaction pattern identified from molecular docking. Key words: cheminformatics, drug design, drug discovery, structure-based drug design, virtual screenin