CAJ | 학술논문

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1 ns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.
통과분자대접건립료일계렬함이불갑기린산기단(DFMP)혹이불갑기류산기단(DFMS)적억제제여락안산단백린산지매1B(PTP1B)적상호작용모식,병통과1 ns적분자동역학모의화molecular mechanics/generalized Born surface area(MM/GBSA)방법계산료기결합자유능.계산획득적결합자유능배서화억제제여파매간결합능력배서일치;통과기우주방정적자유능계산방법,획득료억제제여파매잔기간상호작용적신식,저사신식현시DFMP/DFMS기단적부전하중심여PTP1B적221위정안산정전하중심지간적정전상호작용강약결정료차류억제제적활성,진일보적분석환현시위우DFMP/DFMS기단중적불원자혹기타구유괄당원자반경적경건공체원자회증진차류억제제여PTP1B활성위점적결합능력.
Binding models for a series of difluoromethylenephosphonic(DFMP)and difluoromethylenesulfonic (DFMS)acids to protein tyrosine phosphatase 1B(PTP1 B)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 l 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 PTP1 B 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 PTPl B.