Virtual screening identifies lupeol as an allosteric inhibitor of PTP1B
Purpose: PTP1B is significantly increased in the hypothalamus and plays an important role in central leptin resistance of diet induced obesity in rodents. Leptin signaling pathway is activated by the tyrosine phosphorylation of Jak2. PTP1B negatively regulates leptin signaling via dephosphorylating Jak2. Inhibition of PTP1B in the obesity status may enhance leptin sensitivity, decrease adiposity and prevent excessive weight gain. PTP1B is highly similar to TCPTP. However, deletion of TCPTP in mice leads to immune damage. Current PTP1B inhibitors fail to inhibit PTP1B with high selectivity over TCPTP resulting from targeting the catalytic site. Novel drug design is targeting the allosteric site. Lupeol reduces PTP1B activity in vitro and is potentially a good candidate drug. However the binding site remains unclear. This study presents a combination of docking and molecular dynamics simulations to predict and characterize the binding mode of lupeol to PTP1B. Methods: Molecular docking and molecular dynamics are applied to predict the binding site and simulate the PTP1B-lupeol complex. Various mutagenesis of specific residue in PTP1B (n=3) are used in enzymatic assay to validate the predicted interactions. Results: The preliminary data confirm lupeol binding to the allosteric site which is close to the former reported allosteric site about 20Å away from the catalytic site. The binding properties of lupeol and lupeol-like ligands are reported. The data also reveal the important hydrogen bonding and non-polar interactions. The results, together with experimental data, suggest that lupeol is an allosteric inhibitor. Conclusion: This research demonstrates lupeol as an allosteric PTP1B inhibitor and attracts more attention to render the lupeol structure to produce more potent and selective inhibitors.