title: Structure-based approaches for the design of benzimidazole-2-carbamate derivatives as tubulin polymerization inhibitors.
abstract: 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 (βIII) β-tubulin isotypes in breast and lung cancers and the highly expressed class VI (βVI) 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-, βIII-, and βVI-tubulin isotypes. Our results demonstrate that Ala198 in the βVI 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 βIII-BzC complexes were observed; however, Ser239 in the βIII 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.
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, CDMX, México, Mexico.|Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, CDMX, México, Mexico.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Aguayo-Ortiz
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, CDMX, México, Mexico.
authors.forename: Lucia
authors.initials: L
authors.lastname: Cano-González
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, CDMX, México, Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Castillo
authors.affiliation: Facultad de Química, Departamento de Farmacia, Universidad Nacional Autónoma de México, CDMX, México, Mexico.
authors.forename: Alicia
authors.initials: A
authors.lastname: Hernández-Campos
authors.affiliation: Facultad de Química, Departamento de Fisicoquímica, Universidad Nacional Autónoma de México, CDMX, México, Mexico.
authors.forename: Laura
authors.identifier: 0000-0003-2495-1946
authors.initials: L
authors.lastname: Dominguez
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001562:Benzimidazoles; D002219:Carbamates; D008024:Ligands; D014404:Tubulin; D050257:Tubulin Modulators
keywords: anticancer therapy; benzimidazole-2-carbamate derivatives; docking; molecular dynamics; β-tubulin isotypes