How to Deal with Low-Resolution Target Structures: Using SAR, Ensemble Docking, Hydropathic Analysis, and 3D-QSAR to Definitively Map the 伪尾-Tubulin Colchicine Site

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• 作者：Chenxiao Da ; Susan L. Mooberry ; John T. Gupton ; Glen E. Kellogg
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：September 26, 2013
• 年：2013
• 卷：56
• 期：18
• 页码：7382-7395
• 全文大小：887K
• 年卷期：v.56,no.18(September 26, 2013)
• ISSN：1520-4804

文摘

伪尾-Tubulin colchicine site inhibitors (CSIs) from four scaffolds that we previously tested for antiproliferative activity were modeled to better understand their effect on microtubules. Docking models, constructed by exploiting the SAR of a pyrrole subset and HINT scoring, guided ensemble docking of all 59 compounds. This conformation set and two variants having progressively less structure knowledge were subjected to CoMFA, CoMFA+HINT, and CoMSIA 3D-QSAR analyses. The CoMFA+HINT model (docked alignment) showed the best statistics: leave-one-out q² of 0.616, r² of 0.949, and r²_pred (internal test set) of 0.755. An external (tested in other laboratories) collection of 24 CSIs from eight scaffolds were evaluated with the 3D-QSAR models, which correctly ranked their activity trends in 7/8 scaffolds for CoMFA+HINT (8/8 for CoMFA). The combination of SAR, ensemble docking, hydropathic analysis, and 3D-QSAR provides an atomic-scale colchicine site model more consistent with a target structure resolution much higher than the 3.6 脜 available for 伪尾-tubulin.