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Virtual screening identifies lupeol as an allosteric inhibitor of PTP1B

Conference Paper


Abstract


  • 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.

Publication Date


  • 2013

Citation


  • Jin, T. T., Yu, H. B. & Huang, X. F. (2013). Virtual screening identifies lupeol as an allosteric inhibitor of PTP1B. 33rd Meeting of the Australian Neuroscience Society: Program, Abstracts & List of Registrants (pp. 122-122). Australia: ANS.

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/905

Start Page


  • 122

End Page


  • 122

Place Of Publication


  • Australia

Abstract


  • 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.

Publication Date


  • 2013

Citation


  • Jin, T. T., Yu, H. B. & Huang, X. F. (2013). Virtual screening identifies lupeol as an allosteric inhibitor of PTP1B. 33rd Meeting of the Australian Neuroscience Society: Program, Abstracts & List of Registrants (pp. 122-122). Australia: ANS.

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/905

Start Page


  • 122

End Page


  • 122

Place Of Publication


  • Australia