Discovery of novel DPP IV inhibitors: application of pharmacophore-based virtual screening

Dipeptidyl peptidase IV (DPP-IV) is a potential drug target for type-2 diabetes and DPP-IV inhibitors are known to efficiently improve glucose tolerance. In the present study, pharmacophore model for a set of 29 DPP-IV inhibitors was generated by ligand-based pharmacophore generation process. The best hypothesis, hypo 1, consisting of four chemical features, namely, one hydrogen bond donor, one hydrogen bond acceptor, one hydrophobe and one ring aromatic was validated by cost function analysis, test set prediction and Fischer test. The validated pharmacophore model was then used for searching new lead compounds from Maybridge and NCI database. Four compounds (CD01797, CD06202, CD02493, and AW01077) from Maybridge database and three compounds (NSC997, NSC2450, and NSC5815) from NCI database were identified as structurally diverse druggable novel leads with nM activity against DPP-IV.