新型二氟甲基磷酸类酪氨酸蛋白磷酸酯酶1B抑制剂的分子动力学模拟和结合自由能计算(英文)

Molecular Dynamics Simulations and Free Energy Calculations of a Novel Series of Protein Tyrosine Phosphatase 1B Difluoromethylenephosphonic Acid Inhibitors

通过分子对接建立了一系列含二氟甲基磷酸基团(DFMP)或二氟甲基硫酸基团(DFMS)的抑制剂与酪氨酸蛋白磷酸酯酶1B(PTP1B)的相互作用模式,并通过1ns的分子动力学模拟和molecular mechanics/generalized Born surface area(MM/GBSA)方法计算了其结合自由能.计算获得的结合自由能排序和抑制剂与靶酶间结合能力排序一致;通过基于主方程的自由能计算方法,获得了抑制剂与靶酶残基间相互作用的信息,这些信息显示DFMP/DFMS基团的负电荷中心与PTP1B的221位精氨酸正电荷中心之间的静电相互作用强弱决定了此类抑制剂的活性,进一步的分析还显示位于DFMP/DFMS基团中的氟原子或其他具有适当原子半径的氢键供体原子会增进此类抑制剂与PTP1B活性位点的结合能力.

Binding models for a series of difluoromethylenephosphonic （DFMP） and difluoromethylenesulfonic （DFMS） acids to protein tyrosine phosphatase 1B （PTP1B） were studied by molecular docking,molecular dynamics （MD） simulations,and free energy calculations. Binding free energies were computed using the molecular mechanics/ generalized Born surface area （MM/GBSA） methodology based on 1 ns MD simulations. The order of affinities for the studied inhibitors can be accurately predicted using previously predicted binding free energies. Inhibitor/residue interaction profiles for all inhibitors were systematically generated using MM/GBSA free energy decomposition analysis. Inhibitor/residue interaction profiles demonstrated that electrostatic interactions between the negative charge center of DFMP/DFMS groups and Arg221 of PTP1B are a crucial part of the studied molecule affinities. Furthermore,the fluorine atom or other hydrogen bonding donor atoms with appropriate radii will improve inhibitor binding to the primary binding site of PTP1B.