Unlocking the Potential of Pyrrolidine Derivatives as Antidiabetic Agents: Insights from Physicochemical Analysis, Molecular Docking, ADMET, and DFT Studies

Abstract This study investigates the antidiabetic potential of pyrrolidine‐based derivatives using an integrated computational approach comprising molecular docking, physicochemical profiling, ADMET analysis, DFT, and topological evaluations. Out of 65 hypothesized derivatives, 27 adhered to Lipinski's Rule, demonstrating the oral drug‐likeness. ADMET screening further shortlisted 7 compounds ( 6l, 8l, 9e, 9h, 9k, 9l, and 9n ) that exhibited favorable absorption (HIA: 0.708–0.996), moderate plasma protein binding (23.82–76.37%), non‐inhibition of major CYP450 isoforms (1A2, 2C19, 2C9, 2D6, and 3A4), and nontoxic profiles with no predicted carcinogenicity, mutagenicity, or cardiotoxicity. Docking studies revealed that three derivatives exhibited the strongest binding affinities: 9h : –8.01, –7.06, –8.1 kcal/mol; 9k : –8.2, –7.88, –8.2 kcal/mol and 9l : –8.03, –7.4, –7.39 kcal/mol, for α‐amylase, α‐glucosidase, DPP‐IV, respectively, all of which surpassed the standards acarbose and vildagliptin. NCI and docking pose analysis highlighted stable hydrogen bonding, π–π stacking, and π–alkyl interactions, reinforcing their strong binding stabilities. Moreover, DFT calculations were performed for the three top‐ranked derivatives ( 9h, 9k , and 9l ). Overall, these three derivatives developed as the most promising candidates amid all the assessed pyrrolidine derivatives for their binding affinity for all, results showed lower ∆Egap values ( 9h : 3.2920 eV, 9k : 5.1475 eV, 9l : 5.4148 eV) than vildagliptin (6.5511 eV), indicating higher polarizability, reactivity, and charge transfer potential. Electrophilicity indices (ω) of 0.0030, 0.0115, and 0.0138 for 9h, 9k , and 9l , respectively, suggested significant biological potential. Topological analyses revealed electron localization at electrophilic sites and delocalization over π‐systems, supporting reactivity and structural stability. Collectively, these findings highlight 9h, 9k, and 9l as promising antidiabetic candidates.