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Structure‐based approaches for the design of benzimidazole‐2‐carbamate derivatives as tubulin polymerization inhibitors
Author(s) -
AguayoOrtiz Rodrigo,
CanoGonzález Lucia,
Castillo Rafael,
HernándezCampos Alicia,
Dominguez Laura
Publication year - 2017
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12926
Subject(s) - tubulin , nocodazole , isotype , microtubule , benzimidazole , microtubule polymerization , chemistry , biology , computational biology , biochemistry , microbiology and biotechnology , immunology , antibody , cytoskeleton , cell , monoclonal antibody , organic chemistry
Microtubules are highly dynamic assemblies of α/β‐tubulin heterodimers whose polymerization inhibition is among one of the most successful approaches for anticancer drug development. Overexpression of the class I (βI) and class III (β III ) β‐tubulin isotypes in breast and lung cancers and the highly expressed class VI (β VI ) β‐tubulin isotype in normal blood cells have increased the interest for designing specific tubulin‐binding anticancer therapies. To this end, we employed our previously proposed model of the β‐tubulin–nocodazole complex, supported by the recently determined X‐ray structure, to identify the fundamental structural differences between β‐tubulin isotypes. Moreover, we employed docking and molecular dynamics ( MD ) simulations to determine the binding mode of a series of benzimidazole‐2‐carbamete (BzC) derivatives in the βI‐, β III ‐, and β VI ‐tubulin isotypes. Our results demonstrate that Ala198 in the β VI isotype reduces the affinity of BzCs, explaining the low bone marrow toxicity for nocodazole. Additionally, no significant differences in the binding modes between βI‐ and β III ‐BzC complexes were observed; however, Ser239 in the β III isotype might be associated with the low affinity of BzCs to this isotype. Finally, our study provides insight into the β‐tubulin–BzC interaction features essential for the development of more selective and less toxic anticancer therapeutics.