How to deal with low-resolution target structures: Using SAR, ensemble docking, hydropathic analysis, and 3D-QSAR to definitively map the αβ-tubulin colchicine site

Chenxiao Da, Susan L. Mooberry, John T. Gupton, Glen E. Kellogg

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

αβ-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 r2pred (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 Å available for αβ-tubulin.

Original languageEnglish (US)
Pages (from-to)7382-7395
Number of pages14
JournalJournal of Medicinal Chemistry
Volume56
Issue number18
DOIs
StatePublished - Sep 26 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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