Molecular insight of isotypes specific ß-tubulin interaction of tubulin heterodimer with noscapinoids.
J Comput Aided Mol Des
; 28(7): 751-63, 2014 Jul.
Article
em En
| MEDLINE
| ID: mdl-24916062
Noscapine and its derivatives bind stoichiometrically to tubulin, alter its dynamic instability and thus effectively inhibit the cellular proliferation of a wide variety of cancer cells including many drug-resistant variants. The tubulin molecule is composed of α- and ß-tubulin, which exist as various isotypes whose distribution and drug-binding properties are significantly different. Although the noscapinoids bind to a site overlapping with colchicine, their interaction is more biased towards ß-tubulin. In fact, their precise interaction and binding affinity with specific isotypes of ß-tubulin in the αß-heterodimer has never been addressed. In this study, the binding affinity of a panel of noscapinoids with each type of tubulin was investigated computationally. We found that the binding score of a specific noscapinoid with each type of tubulin isotype is different. Specifically, amino-noscapine has the highest binding score of -6.4, -7.2, -7.4 and -7.3 kcal/mol with αßI, αßII, αßIII and αßIV isotypes, respectively. Similarly 10 showed higher binding affinity of -6.8 kcal/mol with αßV, whereas 8 had the highest binding affinity of -7.2, -7.1 and -7.2 kcal/mol, respectively with αßVI, αßVII and αßVIII isotypes. More importantly, both amino-noscapine and its clinical derivative, bromo-noscapine have the highest binding affinity of -46.2 and -38.1 kcal/mol against αßIII (overexpression of αßIII has been associated with resistance to a wide range of chemotherapeutic drugs for several human malignancies) as measured using MM-PBSA. Knowledge of the isotype specificity of the noscapinoids may allow for development of novel therapeutic agents based on this class of drugs.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Tubulina (Proteína)
/
Isoformas de Proteínas
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Neoplasias
/
Noscapina
Limite:
Humans
Idioma:
En
Revista:
J Comput Aided Mol Des
Assunto da revista:
BIOLOGIA MOLECULAR
/
ENGENHARIA BIOMEDICA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Índia
País de publicação:
Holanda