Combined molecular dynamics and continuum solvent approaches (MM-PBSA/GBSA) to predict noscapinoid binding to gamma-tubulin dimer

摘要

gamma-tubulin plays crucial role in the nucleation and organization of microtubules during cell division. Recent studies have also indicated its role in the regulation of microtubule dynamics at the plus end of the microtubules. Moreover, gamma-tubulin has been found to be over-expressed in many cancer types, such as carcinomas of the breast and glioblastoma multiforme. These studies have led to immense interest in the identification of chemical leads that might interact with gamma-tubulin and disrupt its function in order to explore gamma-tubulin as potential chemotherapeutic target. Recently a colchicine-interacting cavity was identified at the interface of gamma-tubulin dimer that might also interact with other similar compounds. In the same direction we theoretically investigated binding of a class of compounds, noscapinoids (noscapine and its derivatives) at the interface of the gamma-tubulin dimer. Molecular interaction of noscapine and two of its derivatives, amino-noscapine and bromo-noscapine, was investigated by molecular docking, molecular dynamics simulation and binding free energy calculation. All noscapinoids displayed stable interaction throughout simulation of 25 ns. The predictive binding free energy (Delta G(bind)) indicates that noscapinoids bind strongly with the gamma-tubulin dimer. However, bromo-noscapine showed the best binding affinity (Delta G(bind) = -37.6 kcal/mol) followed by noscapine (Delta G(bind) = -29.85 kcal/mol) and amino-noscapine (Delta G(bind) = -23.99 kcal/mol) using the MM-PBSA method. Similarly using the MM-GBSA method, bromo-noscapine showed highest binding affinity (Delta G(bind) = -43.64 kcal/mol) followed by amino-noscapine (Delta G(bind) = -37.56 kcal/mol) and noscapine (Delta G(bind) = -34.57 kcal/mol). The results thus generate compelling evidence that these noscapinoids may hold great potential for preclinical and clinical evaluation.