Santoshi Seneha, Naik Pradeep K
Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Distt., Solan, 173 234, Himachal Pradesh, India.
J Comput Aided Mol Des. 2014 Jul;28(7):751-63. doi: 10.1007/s10822-014-9756-9. Epub 2014 Jun 11.
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.
那可丁及其衍生物以化学计量方式与微管蛋白结合，改变其动态不稳定性，从而有效抑制多种癌细胞（包括许多耐药变体）的细胞增殖。微管蛋白分子由α-微管蛋白和β-微管蛋白组成，它们以多种亚型存在，其分布和药物结合特性有显著差异。尽管那可丁类化合物与秋水仙碱结合于重叠位点，但其相互作用更倾向于β-微管蛋白。事实上，它们与αβ-异二聚体中β-微管蛋白特定亚型的确切相互作用和结合亲和力从未得到研究。在本研究中，通过计算研究了一组那可丁类化合物与每种微管蛋白的结合亲和力。我们发现特定那可丁类化合物与每种微管蛋白亚型的结合分数不同。具体而言，氨基那可丁与αβI、αβII、αβIII和αβIV亚型的结合分数分别为-6.4、-7.2、-7.4和-7.3千卡/摩尔，为最高。同样，化合物10与αβV的结合亲和力较高，为-6.8千卡/摩尔，而化合物8与αβVI、αβVII和αβVIII亚型的结合亲和力分别为-7.2、-7.1和-7.2千卡/摩尔，为最高。更重要的是，使用MM-PBSA测定，氨基那可丁及其临床衍生物溴代那可丁对αβIII的结合亲和力最高，分别为-46.2和-38.1千卡/摩尔（αβIII的过表达与多种人类恶性肿瘤对多种化疗药物的耐药性相关）。了解那可丁类化合物的亚型特异性可能有助于开发基于此类药物的新型治疗剂。
