Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 60612, USA.
J Mol Model. 2009 Dec;15(12):1463-79. doi: 10.1007/s00894-009-0498-x. Epub 2009 May 14.
Molecular modeling and docking studies along with three-dimensional quantitative structure relationships (3D-QSAR) studies have been used to determine the correct binding mode of glycogen synthase kinase 3beta (GSK-3beta) inhibitors. The approaches of comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) are used for the 3D-QSAR of 51 substituted benzofuran-3-yl-(indol-3-yl)maleimides as GSK-3beta inhibitors. Two binding modes of the inhibitors to the binding site of GSK-3beta are investigated. The binding mode 1 yielded better 3D-QSAR correlations using both CoMFA and CoMSIA methodologies. The three-component CoMFA model from the steric and electrostatic fields for the experimentally determined pIC(50) values has the following statistics: R(2)(cv) = 0.386 nd SE(cv) = 0.854 for the cross-validation, and R(2) = 0.811 and SE = 0.474 for the fitted correlation. F (3,47) = 67.034, and probability of R(2) = 0 (3,47) = 0.000. The binding mode suggested by the results of this study is consistent with the preliminary results of X-ray crystal structures of inhibitor-bound GSK-3beta. The 3D-QSAR models were used for the estimation of the inhibitory potency of two additional compounds.
分子建模和对接研究以及三维定量构效关系（3D-QSAR）研究已被用于确定糖原合酶激酶 3β（GSK-3β）抑制剂的正确结合模式。比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）方法被用于 51 个取代的苯并呋喃-3-基-（吲哚-3-基）马来酰亚胺作为 GSK-3β抑制剂的 3D-QSAR 研究。研究了抑制剂与 GSK-3β结合位点的两种结合模式。结合模式 1 采用 CoMFA 和 CoMSIA 方法均产生了更好的 3D-QSAR 相关性。来自立体和静电场的三组分 CoMFA 模型用于预测实验测定的 pIC（50）值，其统计数据如下：交叉验证的 R（2）（cv）= 0.386 nd SE（cv）= 0.854，拟合相关性的 R（2）= 0.811 和 SE = 0.474。F（3,47）= 67.034，R（2）的概率为 0（3,47）= 0.000。该研究结果提示的结合模式与抑制剂结合的 GSK-3β的初步 X 射线晶体结构结果一致。3D-QSAR 模型用于估计另外两种化合物的抑制活性。
