Xiao Aijing, Zhang Zhuoyong, An Liying, Xiang Yuhong
Department of Chemistry, Capital Normal University, Beijing 100037, People's Republic of China.
J Mol Model. 2008 Feb;14(2):149-59. doi: 10.1007/s00894-007-0264-x. Epub 2008 Jan 3.
3D-QSAR and molecular docking analysis were performed to explore the interaction of estrogen receptors (ERalpha and ERbeta) with a series of 3-arylquinazolinethione derivatives. Using the conformations of these compounds revealed by molecular docking, CoMFA analysis resulted in the first quantitative structure-activity relationship (QSAR) and first quantitative structure-selectivity relationship (QSSR) models predicting the inhibitory activity against ERbeta and the selectivity against ERá. The q(2) and R(2) values, along with further testing, indicate that the obtained 3D-QSAR and 3D-QSSR models will be valuable in predicting both the inhibitory activity and selectivity of 3-arylquinazolinethione derivatives for these protein targets. A set of 3D contour plots drawn based on the 3D-QSAR and 3D-QSSR models reveal modifications of substituents at C2 and C5 of the quinazoline which my be useful to improve both the activity and selectivity of ERbeta/ ERalpha. Results showed that both the steric and electrostatic factors should appropriately be taken into account in future rational design and development of more active and more selective ERbeta inhibitors for the therapeutic treatment of osteoporosis.
进行了3D-QSAR和分子对接分析，以探究雌激素受体（ERα和ERβ）与一系列3-芳基喹唑啉硫酮衍生物之间的相互作用。利用分子对接揭示的这些化合物的构象，比较分子场分析（CoMFA）得出了首个预测对ERβ抑制活性和对ERα选择性的定量构效关系（QSAR）模型和首个定量构-选择性关系（QSSR）模型。q(2)和R(2)值以及进一步的测试表明，所获得的3D-QSAR和3D-QSSR模型对于预测3-芳基喹唑啉硫酮衍生物对这些蛋白质靶点的抑制活性和选择性具有重要价值。基于3D-QSAR和3D-QSSR模型绘制的一组3D等高线图揭示了喹唑啉C2和C5位取代基的修饰情况，这可能有助于提高ERβ/ERα的活性和选择性。结果表明，在未来合理设计和开发用于骨质疏松症治疗的更具活性和选择性的ERβ抑制剂时，应适当考虑空间和静电因素。
