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

Abstract

γ-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, γ-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 γ-tubulin and disrupt its function in order to explore γ-tubulin as potential chemotherapeutic target. Recently a colchicine-interacting cavity was identified at the interface of γ-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 γ-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 (ΔGbind) indicates that noscapinoids bind strongly with the γ-tubulin dimer. However, bromo-noscapine showed the best binding affinity (ΔGbind = -37.6 kcal/mol) followed by noscapine (ΔGbind = -29.85 kcal/mol) and amino-noscapine (ΔGbind = -23.99 kcal/mol) using the MM-PBSA method. Similarly using the MM-GBSA method, bromo-noscapine showed highest binding affinity (ΔGbind = -43.64 kcal/mol) followed by amino-noscapine (ΔGbind = -37.56 kcal/mol) and noscapine (ΔGbind = -34.57 kcal/mol). The results thus generate compelling evidence that these noscapinoids may hold great potential for preclinical and clinical evaluation.

Keywords: MM-GBSA; MM-PBSA; free energy calculation; molecular docking; molecular dynamics; noscapine; noscapinoids; γ-tubulin.