Structural and Chemical Basis for Anticancer Activity of a Series of β-Tubulin Ligands: Molecular Modeling and 3D QSAR Studies

An important approach to cancer therapy is the design of small molecule modulators that interfere with microtubule dynamics through their specific binding to the beta-subunit of tubulin. In the present work, comparative molecular field analysis (CoMFA) studies were conducted on a series of discodermolide analogs with antimitotic properties. Significant correlation coefficients were obtained (CoMFA((i)), q(2) = 0.68, r(2) = 0.94; CoMFA((ii)), q(2) = 0.63, r(2) = 0.91), indicating the good internal and external consistency of the models generated using two independent structural alignment strategies. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the 3D contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of discodermolide analogs, and should be useful for the design of new specific beta-tubulin modulators with potent anticancer activity.