喹啉类c-Met激酶抑制剂抗胃癌活性的结合模式研究  

The binding mode analysis exploring on the antigastric cancer activity of quinoline derivatives as c-Met kinase inhibitors

作　　者：邵雪雪 史宇杰 刘秀梅 李燕[1,2] SHAO Xue-xue;SHI Yu-jie;LIU Xiu-mei;LI Yan(Key Laboratory of Xinjiang Phytomedicine Resource and Utilization,Ministry of Education,Shihezi University,Shihezi 832003,China;School of Chemical Engineering,Dalian University of Technology,Dalian 116024,China)

机构地区：[1]石河子大学,新疆植物药资源利用教育部重点实验室,新疆石河子832003 [2]大连理工大学化工学院,辽宁大连116024

出　　处：《分子科学学报》2022年第5期396-406,共11页Journal of Molecular Science

基　　金：国家自然科学基金重点资助项目(81530100,KZ0202);石河子大学绿洲学者基金。

摘　　要：本文基于3D-QSAR方法对一系列具有抗人胃癌细胞(MKN-45)生物活性的喹啉类衍生物进行了三维定量构效关系研究.该3D-QSAR方法包括比较分子力场分析方法(CoMFA)和比较分子相似性指数分析方法(CoMSIA).其中,最优的CoMFA(Q^(2)=0.503,R^(2)_(ncv)=0.899,R^(2)_(pre)=0.866)和CoMSIA(Q^(2)=0.616,R^(2)_(ncv)=0.948,R^(2)_(pre)=0.896)模型都具有较好的可靠性和预测能力.此外,我们借助此模型进行了分子对接研究,深入探究了配体小分子与c-Met受体蛋白之间的结合作用关系.研究结果表明,最优CoMFA模型的三维等势线图形象阐述了位阻和静电基团对小分子抑制剂活性的影响.同时最优CoMSIA模型的三维等势线图不仅阐述了位阻和静电基团,还阐述了疏水、氢键供体和受体基团对小分子抑制剂活性的影响.c-Met抑制剂的R_(1)和R_(3)取代基可作为进一步提高喹啉类c-Met抑制剂活性的主要部位.分子对接分析说明疏水性和氢键在配体小分子和受体结合过程中的重要作用.因此,本文通过研究喹啉类c-Met抑制剂的结构特点及其与喹啉类c-Met蛋白的结合机制,为今后合成新型高效的抗胃癌药物的设计和开发提供理论指导.At present,gastric cancer is a malignant tumor with the fifth incidence,and has jumped to the third leading cause of lethal mortality by neoplasms worldwide.Observational studies have found that c-Met kinase plays a crucial role in the development and progression of stomach neoplastic disease,has now become an extremely potential target for the targeted treatment of gastric cancer.In the present study,based on 3D-QSAR methods,a three-dimensional quantitative structure-activity relationship model was established for a series of quinoline c-Met inhibitor molecules with known anti-human gastric cancer cells(MKN-45).Herein,the proposed 3D-QSAR method specifically includes the comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)approaches.Furthermore,for the obtained results,it has been remarkably shown that the optimal CoMFA(Q^(2)=0.503,R^(2)_(ncv)=0.899,R^(2)_(pre)=0.866)and CoMSIA(Q^(2)=0.616,R^(2)_(ncv)=0.948,R^(2)_(pre)=0.896)models exhibit proper reliability and predictive ability.Further,with the help of this model,the molecular docking analysis was carried out to give a deeper look into the binding relationship between the smallmolecule ligands(c-Met kinase inhibitors)and c-Met protein(receptor).Results demonstrate that the effect of steric hindrance and electrostatic groups on the activity of small molecule inhibitors is illustrated in the three-dimensional isopotential diagram of the optimal CoMFA model.At the same time,the optimal CoMSIA model of three-dimensional isopotential plot not only describes the steric hindrance and electrostatic groups but also describes the influence of hydrophobic,hydrogen bond donor,and receptor groups on the activity of small molecule inhibitors.And,the R_(1)andR_(3)substituents of inhibitors are the main sites to further enhance the activity of quinoline c-Met inhibitors.Moreover,our molecular docking results further indicate that hydrophobic interactions and H-bonds play an extremely important role in the binding process of

关 键 词：胃癌 C-MET蛋白 喹啉类衍生物 三维定量构效关系 分子对接 

分 类 号：O626[理学—有机化学]