嘌呤环类mTOR免疫抑制剂的三维定量构效关系研究

3D-QSAR studies of purine derivatives as mTOR inhibitors

目的通过构建嘌呤环类衍生物与哺乳动物雷帕霉素靶蛋白(m TOR)的分子对接模型,并基于分子对接建立可预测性强的三维定量构效关系(3D-QSAR)模型,探讨此类化合物免疫抑制作用的分子机理,为设计新型嘌呤环类m TOR受体拮抗剂奠定理论基础。方法本实验采用Surflex-dock研究44个嘌呤环类衍生物与m TOR的分子对接模式,采用比较分子力场分析法(Co MFA)和比较分子相似性指数分析法(Co MSIA)对嘌呤环类衍生物进行3D-QSAR研究,建立具有良好预测能力的模型。结果Surflex-dock结果显示,此类分子与m TOR的ASP2195、TYR2225、VAL2240等活性功能残基具有氢键作用,嘌呤母环占据了活性口袋的连接链区形成疏水和范德华相互作用,从而发挥免疫抑制作用。Co MFA模型的q2=0.8,r2=0.976,最佳主成分为5,立体场和静电场对活性的贡献为59%和41%;Co MSIA模型的q2=0.679,r2=0.965,最佳主成分为6,立体场、静电场、疏水场、氢键供体场和受体场对活性的贡献分别为25.9%、9.5%、28.4%、24.7%和11.4%。结论基于嘌呤环类衍生物所建立的3D-QSAR模型的q2均大于0.5,证明此模型具有良好的预测能力。3D-QSAR结果分析和分子对接相一致,疏水场、立体场和氢键作用对嘌呤环类分子的免疫抑制活性影响最大,为设计新型靶向性嘌呤环类m TOR受体拮抗剂奠定了理论基础。

m TOR receptor plays an important role in the treatment of immune diseases. In this study,surflex-dock was applied to characterize the interactions between 44 purine derivatives and m TOR receptor.3D-QSAR models were established by Co MFA and Co MSIA methods. Surflex-dock analysis displayed that ligandsand m TOR interacted with each other via several residues such as ASP2195, TYR2225 and VAL2240, which had akey effect on hydrogen bonds. The purine ring occupied the connecting link of active pocket to form hydrophobic andVDW interactions. Meanwhile, the 3D-QSAR model（Co MFA with q2=0.8, r2=0.976, n=5; Co MSIA with q2=0.679, r2=0.965, n=6） had a good predictability. In sum, 3D-QSAR result combined with Surflex-dock analysis can be appliedto design novel purine derivatives with higher immune activity.