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

Content Provider	Springer Nature Link
Author	Santoshi, Seneha Naik, Pradeep K.
Copyright Year	2014
Abstract	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$_{I}$, αβ$_{II}$, αβ$_{III}$ and αβ$_{IV}$ isotypes, respectively. Similarly 10 showed higher binding affinity of −6.8 kcal/mol with αβ$_{V}$, whereas 8 had the highest binding affinity of −7.2, −7.1 and −7.2 kcal/mol, respectively with αβ$_{VI}$, αβ$_{VII}$ and αβ$_{VIII}$ 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$_{III}$ (overexpression of αβ$_{III}$ 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.
Starting Page	751
Ending Page	763
Page Count	13
File Format	PDF
ISSN	0920654X
Journal	Journal of Computer-Aided Molecular Design
Volume Number	28
Issue Number	7
e-ISSN	15734951
Language	English
Publisher	Springer International Publishing
Publisher Date	2014-06-11
Publisher Place	Cham
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Noscapinoids Tubulin Isotypes Binding affinity MD simulation Physical Chemistry Computer Applications in Chemistry Animal Anatomy / Morphology / Histology
Content Type	Text
Resource Type	Article
Subject	Drug Discovery Physical and Theoretical Chemistry Computer Science Applications

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