CoMFA, HQSAR and molecular docking studies of butitaxel analogues with ?-tubulin

Abstract

Results from biochemical analyses for a series of 20 butitaxel analogues, paclitaxel and docetaxel were used to build two- and three-dimensional quantitative structure-activity relationship (QSAR) models in order to investigate the properties associated with microtubule assembly and stabilization. A comparative molecular field analysis (CoMFA) model was built using steric and electrostatic fields. The CoMFA model yielded an r2 of 0.943 and a cross-validated r2 (i.e. q2) of 0.376. Hologram quantitative structure-activity relationship (HQSAR) modeling of these same data generated an r2 of 0.919 and a q2 of 0.471. Contour maps used to visualize the steric and electrostatic contributions associated with activity or lack thereof were, as expected, localized to the varied position of the taxane system. Each analogue was docked successfully into a model of beta-tubulin derived from previously determined cryoelectron microscopy analyses of the tubulin alpha/beta heterodimer. All analogues superimposed well with paclitaxel bound to the protein, as well as with each other. Defining the variable region of each structure as the ligand and docking it separately into the paclitaxel site revealed a modest correlation (r2 = 0.53) between activity and docking energy of all the compounds in the dataset. When only the butitaxel derivatives were considered, the correlation increased to 0.61. The mathematical models derived here provide information for the future development of taxanes.

Structural and chemical basis for anticancer activity of a series of²-tubulin ligands: molecular modeling and 3D QSAR studies

“…[19][20][21][22][23][24][25][26] However, there is only a small number of QSAR studies found in the literature for taxoid-site tubulin modulators and, to the best of our knowledge, no 3D QSAR investigation of discodermolide analogs has been reported to date. 25,[27][28][29][30] This proves the importance of QSAR studies involving this class of tubulin modulators.…”

“…[19][20][21][22][23][24][25][26] However, there is only a small number of QSAR studies found in the literature for taxoid-site tubulin modulators and, to the best of our knowledge, no 3D QSAR investigation of discodermolide analogs has been reported to date. 25,[27][28][29][30] This proves the importance of QSAR studies involving this class of tubulin modulators.As part of our ongoing research program aimed at designing new β-tubulin modulators, a rational structurebased design strategy was employed to investigate the molecular recognition patterns required for specific β-tubulin binding, as schematically shown in Figure 2. In the present study, three-dimensional QSAR comparative molecular field analysis (3D QSAR CoMFA) 31 models were developed for a series of synthetic discodermolide analogs using two different structural alignment methods in order to explore the high conformational flexibility of the compounds.…”

Fragment-based QSAR: perspectives in drug design

“…Several HQSAR models for a variety of standard data sets consisting of ligands of important molecular targets have been generated throughout recent years [20,21,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40], including cases where the 3D structure of the target protein was not yet available or the molecular target was unknown. It is important to note that besides predicting accurately property values of untested compounds (e.g., potency, affinity), HQSAR models can also provide useful insights into the relationships between structural fragments (micromolecule) and biological activity [25].…”

Conformers, properties, and docking mechanism of the anticancer drug docetaxel: DFT and molecular dynamics studies

“…Due to its better solubility in water, lower toxicity, and higher efficiency anticancer effects of DTX compared with paclitaxel, the application of DTX is becoming more and more widely used. [7,8] Many research groups have done studies of DTX, including the structure, [9] function, [10] docking mechanism, [11,12] and clinical trials [2] to understand the action of DTX on its microtubule target. These studies have highlighted the relevance of the amino acidic side chain at C13 (see green dot, Fig.…”