Screening of NPASS library to uncover potential Dipeptidyl peptidase-IV enzyme inhibitors using structure-based virtual screening and molecular dynamics.

Diabetes mellitus is a chronic metabolic disorder characterised by hyperglycaemia due to insulin resistance and insufficient insulin production. Currently, multiple drugs exist for managing diabetes mellitus. However, the demand for herbal medicines is still required as the present treatments have a few challenges like toxicity, drug resistance and side effects. Therefore, in order to identify potent natural drug candidates, the NPASS database was selected for structure-based virtual screening. Lipinski's rule of five and PAINs removing filters were applied for pre-processing, prior to actual screening. Subsequently, filtered molecules were subjected to three modes of molecular docking, viz. HTVS, SP and XP, where the topmost 10%, 20% and 30% molecules were selected, respectively, followed by binding free energy calculations. Based on dock score evaluation and protein-ligand interaction analysis, the top five candidates were processed for ADME predictions along with the reference drug, sitagliptin. Out of which, two hits, NPC14706 and NPC319625, and Sitagliptin, showing respective ∆GMMGBSA values of - 49.53, - 50.93, and - 27.97 kcal/mol, respectively, with acceptable pharmacokinetic properties (ADME), were subjected to investigate MD simulation studies of about 100 ns. The MD results revealed that compound NPC14706 showed an average RMSD value of ~ 2.5 nm that remained stable throughout the trajectory, while compound NPC319625 exhibited an average RMSD value of ~ 2.9 nm with some fluctuations in between the trajectory. Therefore, the present study indicated that the lead compound NPC41706 could be further assessed for its potential inhibitory activity against the human DPP-IV enzyme through appropriate in-vitro, ADME and Phytomedicine studies for the management of diabetes mellitus. Graphical abstract: