Ducrot P, Legraverend M, Grierson D S
Institut Curie, Section de Recherche, UMR 176 CNRS, Bât. 110-112, Centre Universitaire, 91405 Orsay Cedex, France.
J Med Chem. 2000 Nov 2;43(22):4098-108. doi: 10.1021/jm000965t.
Several series of cyclin-dependent kinase inhibitors previously prepared in our laboratory were compared using 3D-QSAR (CDK1) and docking (CDK2) techniques. Evaluation of our own library of 93 purine derivatives served to establish the model which was validated by evaluation of an external library of 71 compounds. The best predictions were obtained with the CoMFA standard model (q(2) = 0.68, r(2) = 0.90) and with the CoMSIA combined steric, electrostatic, and lipophilic fields (q(2) = 0.74, r(2) = 0.90). The CDK1 3D-QSAR model was then superimposed to the ATP/CDK2 binding site, giving direct contour maps of the different fields. Although too few compounds were evaluated on CDK5 to derive a 3D-QSAR model, some interesting SARs have been deduced. Comparison of the results obtained from both methods helped with understanding the specific activity of some compounds and designing new specific CDK inhibitors.
使用3D-QSAR（CDK1）和对接（CDK2）技术对我们实验室之前制备的几系列细胞周期蛋白依赖性激酶抑制剂进行了比较。对我们自己的93种嘌呤衍生物文库进行评估，以建立模型，该模型通过对71种化合物的外部文库进行评估来验证。使用CoMFA标准模型（q(2)=0.68，r(2)=0.90）以及CoMSIA结合空间、静电和亲脂性场（q(2)=0.74，r(2)=0.90）获得了最佳预测结果。然后将CDK1 3D-QSAR模型叠加到ATP/CDK2结合位点，给出不同场的直接等高线图。虽然对CDK5评估的化合物太少，无法得出3D-QSAR模型，但已经推导出了一些有趣的构效关系。两种方法所得结果的比较有助于理解某些化合物的特异性活性并设计新的特异性CDK抑制剂。
