MMPs抑制剂咖啡酸苯乙酯衍生物的3D-QSAR及分子对接研究

Study on 3D-QSAR and molecular docking of MMPs inhibitor caffeic acid phenethyl ester derivatives

MMP-2是基底膜降解的关键酶,参与宫颈癌病发的整个过程,被认为是治疗宫颈癌的潜在新靶点。本文采用三维定量构效关系(3D-QSAR)研究32个咖啡酸苯乙酯类化合物与抗宫颈癌肿瘤细胞增殖活性的构效关系,通过比较分子场分析(CoMFA)模型(Q^(2)=0.638,R^(2)=0.972)及分子相似性指数分析(CoMSIA)模型(Q^(2)=0.665,R^(2)=0.975),表明所建立的QSAR模型具有稳定的预测能力。基于上述两种模型设计了18种新型咖啡酸苯乙酯类抑制剂,其中5种化合物具有较好的抗癌活性,抑制活性最强的为WS-1。将WS-1与MMP-2蛋白结合,结合模式显示WS-1主要通过氢键作用及疏水作用与MMP-2蛋白紧密结合,并能有效地占据MMP-2蛋白的结合位点。本研究构建的3D-QSAR模型也为进一步设计治疗宫颈癌其他抑制剂提供了理论参考。

MMP-2 is a key enzyme in the degradation of basement membrane,which is involved in the whole process of cervical cancer.It is considered as a potential new target for the treatment of cervical cancer.In this paper,3D-QSAR was used to study the structure-activity relationship between 32 caffeic acid phenylethyl esters and their anti proliferative activity in cervical cancer cells.By CoMFA model(Q^(2)=0.638,R^(2)=0.972)and CoMSIA model(Q^(2)=0.665,R^(2)=0.975),the QSAR model had stable prediction ability.Based on the above two models,18 novel caffeic acid phenylethyl ester inhibitors were designed,5 compounds had better anticancer activity,and WS-1 had the strongest inhibitory activity.The binding pattern of WS-1 to MMP-2 Protein showed that WS-1 was closely bound to MMP-2 protein through hydrogen bonding and hydrophobic interaction,and could effectively occupy the binding site of MMP-2 protein.3D-QSAR constructed in this study also provided a theoretical reference for the further design of other inhibitors for the treatment of cervical cancer.