title: Molecular insight of isotypes specific β-tubulin interaction of tubulin heterodimer with noscapinoids.
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.
authors.affiliation: Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Distt., Solan, 173 234, Himachal Pradesh, India.
authors.forename: Seneha
authors.initials: S
authors.lastname: Santoshi
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Naik
mesh_terms: D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D009665:Noscapine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry* / Q000378:metabolism; D055503:Protein Multimerization; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism
chemical_list: C561203:9-amino-alpha-noscapine; D020033:Protein Isoforms; D014404:Tubulin; D009665:Noscapine; D003078:Colchicine