维甲类化合物构效关系研究：抗致癌活性的三维构效关系

STUDIES ON THE STRUCTURE-ACTIVITY RELATIONSHIP OF RETINOIDS: 3D-QSAR OF RETINOIDAL ANTI-CARINOGENIC ACTIVITIES

使用比较分子场分析法（ｃｏｍｐａｒａｔｉｖｅｍｏｌｅｃｕｌａｒｆｉｅｌｄａｎａｌｙｓｉｓ，ＣｏＭＦＡ）［１］建立了一个维甲类化合物抗致癌活性的三维构效关系（３Ｄ－ＱＳＡＲ）模型，用交叉验证法（ｃｒｏｓｓ－ｖａｌｉｄａｔｉｏｎ）、和非交叉验证方法（ｎｏｎ－ｃｒｏｓｓ－ｖａｌｉｄａｔｉｏｎ）分别验证和建立的分子场模型，高的交叉验证回归系数（＝０．９０５）说明系列化合物分子周围空间场和静电场分布的差异与其生物活性差异间存在良好的相关性。用这个模型预测在建立模型时没有包括进去的三个化合物的活性，预测值接近实验值，提示该模型有较好的活性预测能力，可用来指导设计新的高活性维甲分子。化合物分子的最低能量构象未必是其活性构象。用得到的化合物最低能量构象进行ＣｏＭＦＡ研究，其交叉验证系数较低（＝０．４２０），不具有统计学意义。但将部分分子的单键微弱旋转，构象能变化控制在２ｋｃａｌ·ｍｏｌ－１之内，其它分子采取最低能量构象，则得到高的交叉验证系数。叠合的配体分子场模拟了配体分子周围的作用环境，反映受体结合部位与配体之间存在相互作用的基团和（或）原子的空间和静电性质，分子场模型在作为预测活性模板的同时也在一定程度上映射出受体结合?

Using comparative molecular field analysis(CoMFA),a 3D-QSAR model of anti-carcinogenicity for a series of retinoids was estamshed.The CoMFA model was validated and built bycross-validation(leave-one-out) and non-cross-validation(randomizing)techniques. The significantPLS cross-validated value(0.905)indicated that the model could be used as a predictive tool forfurther design of retinoids with high activity.The activities of three compounds excluded from thecorrelation analysis were computed using this model,small residues being obtained.Based on the conformers with the lowest energy,no statistical significance existed(=0.405).A performance of minor rotation around a single bond for partial compounds provided the conformerswith the variation in energy limit less than 2 kcal· mol-1,by which a correlation analysis was run witha satisfactory relationship between the perturbed confonners and the activities,this suggested thelowest energy cOnformers to be unlikely the pharmacophoric conformers.Superimposition of ligand fields was carried out to mimic the environment of ligands interactingwith their receptor, and to visualize the steric and electrostatic behaviors of groups and/or atomsbetween ligands and receptor.The molecular field model as a template is able to predict activities and,to some extent,to map the topological and physico-chemical characteristics of receptor.