title: 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.
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 q(2) of 0.616, r(2) of 0.949, and r(2)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 Å available for αβ-tubulin.
authors: Department of Medicinal Chemistry & Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University , Richmond, Virginia 23298-0540, United States.
authors: Chenxiao
authors: C
authors: Da
authors: Susan L
authors: SL
authors: Mooberry
authors: John T
authors: JT
authors: Gupton
authors: Glen E
authors: GE
authors: Kellogg
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D003078:Colchicine / Q000378:metabolism*; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D021281:Quantitative Structure-Activity Relationship; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D014404:Tubulin; D003078:Colchicine
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