Comparative molecular field analysis of colchicine inhibition and tubulin polymerization for combretastatins binding to the colchicine binding site on β-tubulin

A molecular modeling study using Comparative Molecular Field Analysis (CoMFA) was undertaken to develop a predictive model for combretastatin binding to the colchicine binding site of tubulin. Furthermore, we examined the potential contribution of lipophillicity (log P) and molecular dipole moment and were unable to correlate these properties to the observed biological data. In this study we first confirmed that tubulin polymerization inhibition (IC50) correlated (R-2 = 0.92) with [H-3]col chicine displacement. Although these data correlated quite well, we developed two independent models for each set of data to quantify structural features that may contribute to each biological property independently. To develop our predictive model we first examined a series of molecular alignments for the training set and ultimately found that overlaying the respective trimethoxyphenyl rings (A ring) of the analogues generated the best correlated model. The CoMFA yielded a cross-validated R-2 = 0.41 (optimum number of components equal to 5) for the tubulin polymerization model and an R-2 = 0.38 (optimum number of components equal to 5) for [H-3]colchicine inhibition. Final non-cross-validation generated models for tubulin polymerization (R-2 of 0.93) and colchicine inhibition (R-2 of 0.91). These models were validated by predicting both biological properties for compounds not used in the training set. These models accurately predicted the IC50 for tubulin polymerization with an R-2 of 0.88 (n = 6) and those of [H-3]colchicine displacement with an R-2 of 0.80 (n = 7). This study represents the first predictive model for the colchicine binding site over a wide range of combretastatin analogues. (C) 2000 Elsevier Science Ltd. All rights reserved.