Mechanism of action of N-phenyl-N'-(2-chloroethyl)ureas in the colchicine-binding site at the interface between a- and b-tubulin

Authors: Fortin, Sébastien; Wei, Lianhu; Moreau, EmmanuelLabrie, PhilippePetitclerc, Éric; Kotra, Lakshmi P.; C. Gaudreault, René
Abstract: Computational tools such as CoMSIA and CoMFA models reported in a recent study revealed the structure–activity relationships ruling the interactions occurring between hydrophobic N-phenyl-N′-(2-chloroethyl)ureas (CEU) and the colchicine-binding site (C-BS) on βΙΙ-tubulin. Here, we describe the mechanisms involved in the covalent binding of three subsets of CEU derivatives to the C-BS. The FlexiDock experiments confirmed that the interaction of non-covalent portions of the CEU auxophore moiety of CEU is involved in the binding of the drug to the C-BS facilitate the nucleophilic attack of Glu-β198 rather than Cys-β239. In addition, these studies suggest that Cys-β239 together with Asn-α99, Ser-α176, Thr-α177, Leu-β246, Asn-β247, Ala-β248, Lys-β252 and Asn-β256 are implicated in the stabilization of a C-BS–CEU complex prior to the acylation of Glu-β198 by CEU. Our molecular models propose the formation of a stabilized C-BS–CEU complex before the completion of the Glu-β198 acylation; acylation triggering conformational changes of β-tubulin, microtubule depolymerization and anoikis. The computational models presented here might be useful to the design of selective and more potent C-BS inhibitors. Of interest, in vivo acylation of acidic amino acid residues by xenobiotics is an unusual reaction and may open new approaches for the design of irreversible protein inhibitors such as tubulin.
Document Type: Article de recherche
Issue Date: 1 April 2009
Open Access Date: 24 April 2019
Document version: AM
Permalink: http://hdl.handle.net/20.500.11794/34553
This document was published in: Bioorganic and medicinal chemistry, Vol. 17 (10), 3690–3697 (2009)
https://doi.org/10.1016/j.bmc.2009.03.056
Pergamon
Alternative version: 10.1016/j.bmc.2009.03.056
19398206
Collection:Articles publiés dans des revues avec comité de lecture

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