Identification of Potential Pancreatic Lipase Inhibitors from Traditional Chinese Medicines via Molecular Docking, Molecular Dynamics Simulation and in vitro Validation

Obesity is one of the major global public health challenges. Pancreatic lipase (PL) is an important target for obesity management as it plays a key role in lipid absorption. However, the clinical application of synthetic PL inhibitors is limited by adverse effects. Previous studies showed that natural products from traditional Chinese medicines (TCMs) is a promising alternative for developing safe PL inhibitors. In this study, we integrated molecular docking, molecular dynamics (MD) simulations, MM/PBSA binding free energy calculations and in vitro enzymatic assays to systematically screen potential PL inhibitors from TCM constituents. Six compounds with docking scores ranging from −9.9 to −9.0 kcal/mol. MD simulations confirmed the structural stability of six ligand−PL complexes via RMSD, radius of gyration (Rg), hydrogen bond and conformational analysis. MM/PBSA calculations revealed the binding free energies of the six compounds to PL ranged from −21.38±0.40 to −13.33±0.58 kcal/mol. In vitro validation showed five of the six compounds exhibited PL inhibitory activity, among which Hydroxygenkwanin (HYD) was the most potent competitive inhibitor (IC₅₀= 0.128±0.009 mM), followed by Atractylenolide I (ATR-I) (IC50 = 0.584±0.031 mM) and Peiminine (PEI) (IC50 = 0.748±0.042 mM). This study validates the efficiency of the integrated in silico and in vitro strategy for screening natural PL inhibitors and provide valuable reference for the development of novel anti-obesity agents or functional food ingredients.