Tyropeptin硼酸肽类蛋白酶体抑制剂的分子对接、三维定量构效关系及分子设计研究

摘要

作为第二代共价类蛋白酶体抑制剂,硼酸肽类抑制剂由于代谢稳定且具较高的蛋白酶体抑制活性和选择特异性,已成为当前新型抗肿瘤药物的重点研究内容。本文以最近合成的44个Tyropeptin硼酸三肽类蛋白酶体抑制剂为研究对象,采用共价距离约束对该类分子与蛋白酶体进行了分子对接研究。结果表明,该类抑制剂与蛋白酶体的非共价相互作用主要以氢键和疏水作用为主,具体表现为：（1）硼酸基团的羟基与ARG19、LYS33和GLY47的氢键作用;（2）肽链骨架原子与THR21、GLY47和ALA49的氢键作用;（3）R1基团与S1口袋的疏水作用和氢键作用。基于对接构象,对上述分子进行了骨架叠合及随后的比较分子场分析（CoMFA）和比较分子相似性形状指数分析（CoMSIA）。最优模型为包含氢键供体场、疏水场、氢键受体场以及立体场的CoMSIA模型,其最佳主成分数、决定系数r2、标准差S、交互验证系数q2以及外部预测r2pred分别为3、0.882、0.188、0.494以及0.756。在以上研究基础上,以活性最高的3C和6号分子为模板,采用基于遗传算法的结构搜索方法结合分子相似性评价函数对其侧链进行了优化设计。结合Lipinski＂5规则＂和最优CoMSIA模型活性预测结果,最终得到5个目标分子,其预测活性均达到纳摩尔水平。%Recently,as the second generation of 20S proteasome inhibitors,peptide boronic acid derivatives have received much more attentions due to their stable metabolism,strong inhibitory activity,high specificity,and low toxicity.However,the structures of proteasome inhibitors are relatively complex and flexible,which cause troubles for structure-based drug design.In this paper,molecular docking was applied to mechanism study on 44 boronic acid derivatives of tyropeptin inhibitors of 20S proteasome.The results showed that main non-covalent interactions between boronic acid derivatives of tyropeptin and proteasome are as follows：（1） H-bond interactions between OH of boronic acid group and ARG19,LYS33,and GLY47;（2） H-bond interactions between atoms of backbone of peptide and THR21,GLY47,and ALA49;（3） Hydrophobic and H-bond interactions between R1 group and S1 pocket of proteasome.Based on the docking conformers,all 44 samples were aligned according to the sketch atoms and then used for following CoMFA and CoMSIA to obtain the optimal CoMSIA model,of which the number of principal component,determination coefficients（r2）,standard deviation（S）,cross-validated r2（q2）,and determination coefficients for external samples（r2pred） of were 3,0.882,0.188,0.494 and 0.756,respectively.Then,de novo molecular design was performed based on two templates with high activities.GA-based structure search algorism and similarity evaluation function was used to guide the evolution process.Five new molecules were obtained according to the rule of Lipinski and as-predicted activities by the optimal CoMSIA model.The inhibitory activities of them are all at nano level.