Comparative modelling of human β tubulin isotypes and implications for drug binding

Abstract

The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.

Screening Anti-Cancer Drugs against Tubulin using Catch-and-Release Electrospray Ionization Mass Spectrometry

“…However, the distribution of tubulin isotypes is different for all cell types and especially for cancer cells [50]. Therefore, the idea of targeting an isotype of tubulin that is highly expressed in cancer cells and much less so in normal cells would lead to an optimization of treatment efficacy and minimization of side effects [51]. A computational algorithm for such a selection process from a library of tubulin-binding ligands has recently been published [52].…”

The Tubulin Colchicine Domain: a Molecular Modeling Perspective

“…Great efforts in this approach were carried out by Mane and co-workers. [51,52,54,60] They performed homology modeling to obtain the various isoform structures and reported an in silico evaluation (free energy perturbation (FEP) analysis) of a colchicine analogue training set, identifying one candidate which should bind selectively to the abIII isoform. [55] Structure-based drug design Pharmacophore As discussed above, there are several chemical entities that are able to bind tubulin, acting as disrupting agents.…”

Identification of tubulin drug binding sites and prediction of relative differences in binding affinities to tubulin isotypes using digital signal processing

“…It is this varied distribution of tubulin isotypes that provides us with a possible link to their role in the polymerization and stability of MTs. Through a search of available protein sequence databases, we have previously identified a total of 10 unique human b-tubulin isotypes, all of which have related distinct amino acid sequences and are generally well conserved [14]. Despite having very similar sequences, specific regions of higher sequence variability have been identified (see Fig.…”