摘要
本文选取42个2,4-二氨基嘧啶类黏着斑激酶(FAK)小分子抑制剂,分别以比较分子场分析法(CoMFA)与相似性指数分析法(CoMSIA)构建3D-QSAR模型,评价模板分子、公共骨架点、最小能量优化参数、分子构象等因素对模型优化的影响。分析最优模型中立体场、静电场以及氢键等因素对抑制剂活性的影响,并应用分子对接分析该类抑制剂与FAK蛋白的相互作用。结果表明,选择化合物16作为模板分子,骨架A作为公共骨架点,最小能量优化参数中电荷、最大迭代系数、最低能量限定值分别为MMFF94、1000、0.01kcal/mol时所构建的模型最优。以CoMFA和CoMSIA构建的3D-QSAR模型的交叉验证系数(q^(2))分别为0.666和0.736,非交叉验证系数(R^(2))分别为0.990和0.989,表明此模型具有良好的预测能力。分子对接分析显示,其与FAK的氨基酸残基CYS502、ASP564形成了重要的氢键作用,并与周围残基形成了较强的疏水作用。通过3D-QSAR的构建与分子对接分析,可指导2,4-二氨基嘧啶类FAK小分子抑制剂的进一步结构优化设计。
Comparative Molecular Field Analysis(CoMFA) and Comparative Molecular Similarity Indices Analysis(CoMSIA) were used to construct three-dimensional quantitative structure-activity relationship(3D-QSAR) models of 42 2,4-diaminopyrimidine FAK inhibitors. The effect of template molecule, common skeleton points, minimum energy optimization parameter and molecular conformation on model optimization were evaluated. The relationship of stereo field, electrostatic field, and hydrogen bond on the activity of FAK inhibitors were analyzed. Using molecular docking, the interaction between these inhibitors and FAK protein was analyzed. The results indicated that when compound 16 is selected as the template molecule, skeleton A is used as the common skeleton point, and the minimum energy optimization parameters of charge, maximum iteration coefficient and minimum energy limit are MMFF94, 1000 and 0.01 Kcal/mol, respectively, the model constructed is the best. The cross-validation coefficients(q^(2)) of the 3D-QSAR model constructed by CoMFA and CoMSIA were 0.666 and 0.736, the non cross validation coefficients(R^(2)) were 0.990 and 0.989, respectively, indicating good predictions. The effect of introducing substituents at different positions on the activity of FAK inhibitors was directly reflected by the obtained three-dimensional isometric views. The molecular docking analysis showed that hydrogen bonds were formed with CYS502, ASP564, and strong hydrophobic interactions were observed formed with the surrounding residues. The parameters play important roles in the construction of 3 D-QSAR model. The 3D-QSAR models constructed in this study have good predictive abilities. The 3D-QSAR and molecular docking analysis provide the basis for the design, synthesis and structural optimization of 2,4-diaminopyrimidine FAK inhibitors.
作者
杨丹
徐兴莲
张荣红
周孟
Yang Dan;Xu Xinglian;Zhang Ronghong;Zhou Meng(Engineering Research Center of the Ministry of Education for the Development and Application of Ethnic Medicine and Traditional Chinese Medicine of Guizhou Medical University/State Key Laboratory of Efficacy and Utilization of Medicinal Plants,Guiyang,550004;College of Pharmacy,Guizhou Medical University,Gui'an New District,550025;Tissue Engineering and Stem Cell Experimental Center,Guizhou Medical University,Guiyang,550004)
出处
《化学通报》
CAS
CSCD
北大核心
2021年第10期1092-1101,共10页
Chemistry
基金
贵州省科技厅联合项目(黔科合平台人才[2018]5779-13/75)
贵州省科技厅基础研究计划项目(黔科合基础[2020]1Z008)资助
贵州省教育厅青年人才成长项目([2018]174)。
