title: Elucidating the mechanism of action of the clinically approved taxanes: a comprehensive comparison of local and allosteric effects.
abstract: The clinically approved taxanes (paclitaxel, docetaxel and cabazitaxel) target the tubulin protein in microtubules. Despite the clinical success of these agents, the mechanism of action of this class of drugs remains elusive, making rational design of taxanes difficult. Molecular dynamics simulations of these three taxanes with the αβ-tubulin heterodimer examine the similarities and differences in the effects of the drugs on tubulin, probing both local and allosteric effects. Despite their structural similarity, the drugs adopt different conformations in the binding site on β-tubulin. The taxanes similarly increase the helical character of α- and β-tubulins. No correlations are found between microtubule assembly and (i) binding affinity or (ii) the role of the M-loop in enhancing lateral contacts. Instead, changes in intra- and interdimer longitudinal contacts are indicative of the mechanism of action of the taxanes. We find β:H1-S1', and more importantly β:H9 and β:H10, play a role translating the effect of local drug binding in β-tubulin to an allosteric effect in α-tubulin and propose that the displacement of these secondary structures towards α-tubulin may be used as a predictor of the effect of taxanes on the tubulin heterodimers in rational drug design approaches.
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, AB, T6G 2G2, Canada.
authors.forename: Cassandra D M
authors.identifier: http://orcid.org/0000-0003-1754-2044
authors.initials: CD
authors.lastname: Churchill
authors.affiliation: Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, AB, T6G 2G2, Canada.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Klobukowski
authors.affiliation: Department of Oncology, University of Alberta, Cross Cancer Institute 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.|Department of Physics, University of Alberta, 4-181 CCIS, Edmonton, AB, T6G 2E1, Canada.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Tuszynski
mesh_terms: D000495:Allosteric Site / Q000187:drug effects; D000077143:Docetaxel; D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D055503:Protein Multimerization / Q000187:drug effects; D017433:Protein Structure, Secondary / Q000187:drug effects; D043823:Taxoids / Q000737:chemistry / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism*; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; D000077143:Docetaxel; C552428:cabazitaxel; D017239:Paclitaxel
keywords: Taxol; Taxotere; microtubules; molecular dynamics; rational drug design; tubulin