Globisch Christoph, Pajeva Ilza K, Wiese Michael
Institute of Pharmacy, University of Bonn, Germany.
Bioorg Med Chem. 2006 Mar 1;14(5):1588-98. doi: 10.1016/j.bmc.2005.10.058. Epub 2005 Nov 22.
Tariquidar (XR9576) analogs, modulators of cancer multidrug resistance (MDR), were subjected to QSAR and 3D-QSAR analyses. The structural features contributing to anti-MDR activity were identified by the Free-Wilson analysis and pharmacophore search using Hoechst 33342 as a template. 3D-QSAR CoMFA and CoMSIA models were derived and tested. The best models yielded an external predictivity of 0.66-0.75 squared correlation coefficient and outlined HB-acceptor, steric, and hydrophobic fields as the most important 3D properties. On the basis of the QSAR and 3D-QSAR analyses it was suggested that the strong inhibitory potency of the compounds studied is related to the presence of a bulky aromatic ring system with a 3rd positioned heteroatom toward the anthranilamide nucleus in the opposite end of the tetrahydroquinoline group. The results can help in directing the rational design of new generations of potent P-glycoprotein MDR modulators.
他立喹达（XR9576）类似物，即癌症多药耐药性（MDR）调节剂，进行了定量构效关系（QSAR）和三维定量构效关系（3D-QSAR）分析。通过自由威尔逊分析和以Hoechst 33342为模板的药效团搜索，确定了有助于抗MDR活性的结构特征。推导并测试了3D-QSAR比较分子场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）模型。最佳模型的外部预测性相关系数平方为0.66 - 0.75，并勾勒出氢键受体、立体和疏水场是最重要的三维性质。基于QSAR和3D-QSAR分析，表明所研究化合物的强抑制效力与在四氢喹啉基团另一端朝向邻氨基苯甲酰胺核的位置3带有杂原子的庞大芳香环系统的存在有关。这些结果有助于指导新一代强效P-糖蛋白MDR调节剂的合理设计。
