In silico study of therapeutic potential of natural polyphenol derivatives targeting pancreatic lipase

Obesity remains a global health concern, and inhibiting human pancreatic lipase (EC3.1.1.3), a key enzyme in dietary fat breakdown and absorption, is an effective therapeutic approach. However, current lipase inhibitors such as orlistat are often associated with adverse gastrointestinal side effects and poor patient compliance. As a safer and multifunctional alternative, we investigated a library of naturally derived polyphenols known for their enzyme inhibitory activity and metabolic benefits, including anti-inflammatory effects, enhanced insulin sensitivity, and modulation of gut microbiota—offering a synergistic approach to obesity management. This study explores the dynamic and mechanistic inhibitory potential of polyphenol-based HPL inhibitors through an extensive in silico approach, aiming to identify explicit, low-toxicity inhibitors that serve as multi-benefit scaffolds for next-generation anti-obesity therapeutics. Significant binding affinity and interactions with a 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 a stable protein-ligand complex over 100 ns. FEL, PCA, and DCCM analysis also demonstrated these protein-ligand complexes' stable dynamic behavior and conformational changes. Additionally, post-simulation MMPBSA analysis revealed higher binding free energies of − 59.46, − 56.54, and − 48.48 kcal mol⁻¹ for these complexes, indicating the formation of thermodynamically more stable complexes. Their favorable ADMET and drug-likeness pharmacokinetic properties further support their potential as effective HPL inhibitors with the potential for obesity control. The finding highlights (−)-epigallocatechin-3-O-p-coumarate, (+)-catechin-3-O-gallate, and (−)-epicatechin-3-O-(3'-O-methyl gallate) as promising low-toxicity, multi-benefit candidates for obesity management, paving the way for next-generation plant-based therapeutics.