Computational Drug Repurposing Study Identifies Rimegepant as a Promising DPP4 Inhibitor for Type 2 Diabetes

Type 2 diabetes mellitus (T2D) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose regulation, with Dipeptidyl Peptidase 4 (DPP4) being a key therapeutic target. This study aimed to identify potential DPP4 inhibitors among the screened compounds from the approved drug library using curcumin as a matrix through the in-silico approaches. Ligand-based virtual screening (LBVS) was performed using DrugRep software, leading to the identification of ten (10) compounds from the approved drug library. Subsequently, structure-based virtual screening (SBVS), including molecular docking, was conducted to evaluate the binding affinity of these compounds to the DPP4 enzyme. The screened compounds exhibited binding affinities ranging from -7.0 to -9.9 kcal/mol, while the reference compound Sitagliptin showed a binding affinity of -8.3 kcal/mol within the active site of the DPP4 enzyme. Rimegepant emerged as the most promising candidate, exhibiting stronger binding affinity for key residues such as Pro510, Leu514, and Arg560 compared to the reference drug, Sitagliptin, which interacted with Val585, Thr565, Pro475, Gly576, and Arg560. Furthermore, network pharmacology analysis was conducted to investigate the mechanism of action of Rimegepant in modulating key pathways associated with T2D, including DPP4 inhibition, which influences the insulin resistance signaling pathway. Moreover, the physicochemical and pharmacokinetic profiles indicate that Rimegepant possesses favorable drug-like properties. These findings indicate that Rimegepant may have potential as a therapeutic candidate for T2D; however, the study is limited to in-silico analyses. Further molecular dynamics (MD) simulations and experimental validation, including in vitro and in vivo studies, are necessary to confirm its efficacy and safety before any clinical application.