Exploring the DPP IV inhibitory potential: molecular docking and dynamic simulations of pyridine-3-carboxylic acid and pyrrolidine-2-carboxylic acid analogs

Diabetes mellitus remains a global challenge, with Type 2 Diabetes Mellitus (T2DM) prevalence increasing from 4% to 6.4% in the past 30 years. Presently oral hypoglycaemic agents like GLP-1 agonists, biguanides, sulphonylureas, glinides, and thiazolidinediones are employed in clinical practice. Very recently, novel targets including Dipeptidyl peptidase IV (DPP IV), PPAR, GIP, FFA1, and melatonin have been in the limelight for the development of novel treatment strategies. The present study focuses on the development of DPP IV inhibitors through computational approaches. DPP IV, also referred to as CD26 (cluster of differentiation 26) or adenosine deaminase complexing protein 2, is a protein that is encoded by the DPP IV gene in humans. This enzyme is involved in the metabolism of incretin hormones such as glucagon-like peptides (GLP-1). DPP IV inhibitors prevent the degradation of GLP-1, glucose-dependent insulinotropic peptide (GIP), thereby controlling the concentration of glucose in the blood. Considering the safety and efficacy of DPP IV inhibitors newer molecules were designed with better binding affinity with the protein as compared to existing Sitagliptin, and Vildagliptin-like drugs. Derivatives of nicotinic acid and proline were designed and studied using molecular docking and dynamic simulations. Docking results demonstrated that the NA-13 molecule possesses potent binding affinity with target protein 6B1E (-38.1498 kcal/mol) as compared to standard Sitagliptin (-33.3187 kcal/mol). MD simulation studies showcased that there are fewer variations of RMSD and RMSF for 6B1E-NA-13, 6B1E-P1, and 6B1E-P7 complexes, suggesting the potential of the designed DPP IV inhibitors in the management of T2DM.