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

alpha beta-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 subjected to CoMFA, CoMFA+HINT, and CoMSIA docking of all 59 compounds. This conformation set and two SAR of a pyrrole subset and HINT scoring, guided ensemble variants having progressively less structure knowledge were 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(pred)(2) (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 +HINT (8/8 for CoMFA). The combination of SAP., 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 similar to 3.6 angstrom available for alpha beta-tubulin.