Pancreatic Lipase Inhibitors: Mechanistic Foundations, Structural Insights, and Emerging Medicinal Chemistry Strategies

The main dietary triglyceride hydrolyzing catalyst, and a long time pharmacological parameter of decreased dietary caloric intake, is pancreatic lipase (PL). Recent progress in structural biology, high resolution crystalography and computational models has given a new understanding of the catalytic triad of PL and interfacial activation, lid dynamics and stabilization of colipase dependent. These mechanistic underpinnings have facilitated more rational search of the varied classes of inhibitors including covalent β-lactones to reversible natural products (flavonoids, aurones, chalcones) and contemporary synthetic scaffolds like thiazolidinedione, triazole, and multi-target hybrid chemotypes. The mechanism by which the inhibitors interact with the hydrophobic acyl-binding tunnel, oxyanion hole, and aromatic platform around Ser152 is now understood using quantitative structure-activity correlations, molecular docking, molecular dynamics simulations, and pharmacophore models. The new approaches to medicinal chemistry, such as allosteric inhibition of lid movement, partial inhibition to enhance the safety, the investigation of non-2-lactone electrophiles, and AI-assisted scaffold discovery provide avenues to effective, yet safer inhibitors. The enzymatic mechanism, structural biology, SAR trends, and computational methods have been incorporated in this review to present a single framework in designing next-generation pancreatic lipase inhibitors.