Molecular insight of isotypes specific β-tubulin interaction of tubulin heterodimer with noscapinoids.

Santoshi, Seneha; Naik, Pradeep

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 β-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 β-tubulin. In fact, their precise interaction and binding affinity with specific isotypes of β-tubulin in the αβ-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 αβ, αβ, αβ and αβ isotypes, respectively. Similarly 10 showed higher binding affinity of −6.8 kcal/mol with αβ, whereas 8 had the highest binding affinity of −7.2, −7.1 and −7.2 kcal/mol, respectively with αβ, αβ and αβ 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 αβ (overexpression of αβ 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.

DRUG resistance in cancer cells; CANCER cell proliferation; TUBULINS; NOSCAPINE; HETERODIMERS; MOLECULAR dynamics; ANTINEOPLASTIC agents; DRUG derivatives

Journal of Computer-Aided Molecular Design, 2014, Vol 28, Issue 7, p751

0920-654X

Academic Journal

10.1007/s10822-014-9756-9