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

Obesity represents one of the most critical global public health challenges. Pancreatic lipase (PL) serves as a key therapeutic target for obesity control, whereas clinical synthetic PL inhibitors are greatly restricted by adverse reactions. Traditional Chinese medicines (TCMs) have a long-standing history in regulating lipid metabolism and ameliorating obesity-related disorders, and are characterized by remarkable structural diversity, low toxicity, and mild side effects, thus representing a promising source for developing safe and efficient PL inhibitors. In this work, an integrated strategy combining in silico screening and in vitro validation was employed to identify potential PL inhibitors from TCM components, including molecular docking, molecular dynamics simulation, MM/PBSA binding free energy computation, and in vitro enzymatic assay. Six compounds with docking scores ranging from −9.9 to −9.0 kcal/mol were selected for further investigation. Molecular dynamics simulations verified the favorable structural stability of the corresponding ligand–PL complexes, and MM/PBSA calculations demonstrated negative binding free energies from −21.24 ± 0.39 to −12.03 ± 0.40 kcal/mol. In vitro experiments indicated that three compounds (Hydroxygenkwanin, Atractylenolide I, and Peiminine) showed effective PL inhibitory activity, with IC50 values of 0.128 ± 0.009, 0.584 ± 0.031, and 0.748 ± 0.042 mM, respectively. These values are comparable to quercetin (0.231 ± 0.034 mM) but significantly higher than orlistat (0.481 ± 0.023 μM), which is attributed to their non-covalent binding pattern. Collectively, this study validated the reliability of the integrated in silico and in vitro screening strategy, identified three effective pancreatic lipase inhibitors derived from TCMs, established a robust paradigm for the discovery of natural PL inhibitors, and laid a solid foundation for subsequent research on natural anti-obesity agents.