Potential DPP-IV inhibitors for type 2 diabetes mellitus: an integrated computational and experimental pipeline

Dipeptidyl peptidase-IV (DPP-IV) inhibition remains a cornerstone therapeutic strategy for managing type 2 diabetes mellitus (T2DM) by prolonging endogenous incretin hormone activity. However, developing next-generation inhibitors with optimized pharmacokinetic profiles and enhanced target stability remains an ongoing challenge. This study presents a comprehensive, multi-tiered evaluation of gosogliptin and novel PubChem-derived DPP-IV inhibitors (e.g., PubChem 11450633, PubChem 46216692) compared to the clinical benchmark, sitagliptin. Extensive 300-ns molecular dynamics (MD) simulations and MM-GBSA calculations revealed that compounds PubChem 11,450,633 and PubChem 46,216,692 exhibit superior thermodynamic stability and binding affinities (Delta G bind = -48.77 and − 46.76 kcal/mol, respectively) compared to sitagliptin (-44.46 kcal/mol). This outperformance is driven by optimal van der Waals packing, robust electrostatic anchoring to the Glu205/Glu206 dyad, and balanced polar desolvation penalties. In silico ADMET profiling confirmed favorable drug-likeness, high gastrointestinal absorption, and negligible blood-brain barrier permeation. Experimental validation strongly corroborated these computational predictions. Gosogliptin demonstrated a 2.5-fold higher aqueous solubility (0.30 mg/mL) than sitagliptin (0.12 mg/mL) alongside a highly favorable, low-lipophilicity profile (experimental LogP = 0.30). In cell-based functional assays, gosogliptin achieved equipotent GLP-1 protection (around 75% at 100 nM) and exhibited an exceptional safety margin, maintaining cell viability up to 50 micromolar. Collectively, these synergistic computational and experimental findings highlight gosogliptin and specific lead candidates as highly promising, safe, and efficacious DPP-IV inhibitors. The optimized pharmacokinetic and thermodynamic profiles demonstrated in this study strongly warrant their advancement into in vivo preclinical models for next-generation T2DM therapeutics.