Pharmacophore Mapping, Virtual Screening and Molecular Docking Studies of DPP-IV Inhibitors

Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. Chemical features based 3D pharmacophore model for DPP-IV was developed using a training set of 16 structurally diverse known DPP-IV inhibitors using DISCOtech module of Tripos Sybyl X1.2. The best pharmacophore hypothesis, which identified inhibitors with a highest score of 0.5859, tolerance of 0.500 and D-mean of 3.9179, contained five features, namely, one positive nitrogen (PN), one hydrophobic point (HY), two acceptor sites (AS) and one donor atom. The model was further validated by a testing set of 51 known DPP-IV inhibitors. We applied this pharmacophore model to screen NCI database and Maybridge hit finder for potential DPP-IV inhibitors. The hits were docked to DPP-IV with Surflex module of Tripos Sybyl X1.2. Ultimately, 3 moelcules were selected as potential DPP-IV inhibitors for In silico pharmacokinetic and toxicities studies.