State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
J Mol Model. 2011 Dec;17(12):3241-50. doi: 10.1007/s00894-011-1011-x. Epub 2011 Mar 4.
Inhibition of the protein chaperone Hsp90α is a promising approach for cancer therapy. In this work, a molecular modeling study combining pharmacophore model, molecular docking and three-dimensional quantitative structure-activity relationships (3D-QSAR) was performed to investigate a series of pyrazole/isoxazole scaffold inhibitors of human Hsp90α. The pharmacophore model can provide the essential features required for the biological activities of the inhibitors. The molecular docking study can give insight into the binding mode between Hsp90α and its inhibitors. 3D-QSAR based on CoMFA and CoMSIA models were performed from three different strategies for conformational selection and alignment. The receptor-based models gave the most statistically significant results with cross-validated q (2) values of 0.782 and 0.829 and r (2) values of 0.909 and 0.968, for CoMFA and CoMSIA respectively. Furthermore, the 3D contour maps superimposed within the binding site of Hsp90α could help to understand the pivotal interaction and the structural requirements for potent Hsp90α inhibitors. The results show 4-position of pyrazole/isoxazole ring requires bulky and hydrophobic groups, and bulky and electron repulsion substituent of 5-amides is favorable for enhancing activity. This study will be helpful for the rational design of new potent Hsp90α inhibitors.
抑制蛋白质伴侣 Hsp90α 是癌症治疗的一种很有前途的方法。在这项工作中，我们结合药效基团模型、分子对接和三维定量构效关系（3D-QSAR）进行了一项分子建模研究，以研究一系列针对人 Hsp90α 的吡唑/异噁唑骨架抑制剂。药效基团模型可以提供抑制剂生物活性所需的基本特征。分子对接研究可以深入了解 Hsp90α 与其抑制剂之间的结合模式。基于 CoMFA 和 CoMSIA 模型的 3D-QSAR 分别从三个不同的构象选择和对齐策略进行。基于受体的模型给出了最具统计学意义的结果，CoMFA 和 CoMSIA 的交叉验证 q² 值分别为 0.782 和 0.829，r² 值分别为 0.909 和 0.968。此外，在 Hsp90α 结合位点叠加的 3D 等高线图有助于理解关键相互作用和对有效 Hsp90α 抑制剂的结构要求。结果表明，吡唑/异噁唑环的 4 位需要大体积和疏水性基团，5-酰胺的大体积和电子排斥取代基有利于提高活性。这项研究将有助于合理设计新型有效的 Hsp90α 抑制剂。
