Discovery of novel tubulin polymerization inhibitors by utilizing 3D-QSAR, molecular docking and molecular dynamics simulation

Abstract

Tubulin is a potential therapeutic target for cancer. Inhibiting the polymerization of tubulin or promoting the polymerization of tubulin to interfere with the mitotic process of cells, could result to the interruption of cell mitosis, and then lead to apoptosis of tumor cells. In this study, a series of new styrylquinoline tubulin inhibitors were designed as anti-cancer compounds using 3D-QSAR, molecular docking and molecular dynamics (MD) simulation. Two reliable CoMFA (q² = 0.86, r² = 0.934) and CoMSIA (q² = 0.846, r² = 0.938) models of tubulin polymerization inhibitors were established, and molecular docking was used to explore the docking mode of the compounds and receptors. Next, we designed ten new tubulin polymerization inhibitors and predicted their activities using 3D-QSAR model. Molecular docking again revealed important residues for protein–compound interactions, and the results revealed that tubulin polymerization inhibitors had stronger binding affinity with key residues of proteins, such as Ser140, Glu183, Ile171, Thr179, Ala180, etc. The molecular dynamics (MD) simulation further verified the results of molecular docking. This study provides significant guidance for the design of novel tubulin polymerization inhibitors.