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

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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 αβI, αβII, αβIII and αβIV isotypes, respectively. Similarly 10 showed higher binding affinity of −6.8 kcal/mol with αβV, whereas 8 had the highest binding affinity of −7.2, −7.1 and −7.2 kcal/mol, respectively with αβVI, αβVII and αβVIII 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 αβIII (overexpression of αβIII 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.

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Acknowledgments

Authors are thankful to Dr. Harish Joshi, School of Medicine, Emory University, Georgia, USA, for carefully reading the manuscript and for providing constructive criticism. We are greatly indebted to the anonymous reviewers of this manuscript for their helpful suggestions.

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  1. Pradeep K. Naik

    Present address: Department of Biotechnology, Guru Ghasidas Vishwavidyalaya, A Central University, Koni, Bilaspur, 495 009, Chhattisgarh, India

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  1. Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Distt., Solan, 173 234, Himachal Pradesh, India

    Seneha Santoshi & Pradeep K. Naik

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Correspondence to Pradeep K. Naik.

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Santoshi, S., Naik, P.K. Molecular insight of isotypes specific β-tubulin interaction of tubulin heterodimer with noscapinoids. J Comput Aided Mol Des 28, 751–763 (2014). https://doi.org/10.1007/s10822-014-9756-9

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