Polyphenol Inhibition of Human Pancreatic Lipase: An In-Silico Study Towards Obesity Control

Background: Inhibiting human pancreatic lipase (EC3.1.1.3), a key enzyme in dietary fat breakdown and absorption, is an effective therapeutic approach for obesity control. Polyphenols, due to their multifaceted structure, enhance insulin sensitivity, reduce inflammation, and modulate gut microbiota, offering synergistic effects in controlling obesity. Methods: Considering the adverse side effects associated with current anti-obesity therapeutics, we explored a library of polyphenols known for their antiobesity properties to explicitly potent HPL inhibitors through extensive in-silico study including molecular docking, DFT, MD simulation, PCA, DCCM-based conformational analysis and pharmacokinetic analysis. Results: Significant binding affinity and interactions with catalytic triad (SER 152, HIS 263, and ASP 176) of HPL through molecular docking, alongside higher MM/GBSA values of -53.29, -52.76, and -53.37 kcal/mol, identified (-)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (-)-epicatechin-3-O-(3'-O-methyl gallate), respectively, as potent leads. The DFT study and molecular dynamics simulation affirmed the strong reactivity of these compounds in the catalytic site of HPL and stable protein-ligand complex over 100 ns. FEL, PCA, and DCCM analysis also demonstrated these protein-ligand complexes' stable dynamic behavior and conformational changes. Moreover, post-simulation MMPBSA analysis indicated higher binding free energy and favorable ADMET and drug-likeness pharmacokinetic properties asserted these lead potentials as explicit HPL inhibitors with potential for obesity control. Conclusion: To sum up, (-)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (-)-epicatechin-3-O-(3'-O-methyl gallate) are identified as promising HPL inhibitors, with potential application in managing obesity due to their stable interaction with the enzyme and favorable pharmacokinetic characteristics.