Virtual and experimental high throughput screening of substituted hydrazones on β-Tubulin polymerization

Abstract

Microtubule targeting agents that disrupt the dynamic functioning of the mitotic spindle are some of the best chemotherapeutic agents. Interruption of microtubule dynamics through polymerization or depolymerization causes cell arrest leading to apoptosis. We report a novel class of aroylhydrazones with anticancer properties. Tubulin inhibition studies were performed using both computational and biological methods. Docking and pharmacophore mapping showed efficient binding between the ligands and the protein. Tubulin inhibition assay showed the aroylhydrazones to be inhibitors of tubulin polymerization. DFT studies explains the geometrical and electronic properties of the compounds. Furthermore, anticancer studies using lung and liver cancer cell lines gave low IC₅₀ values with the methyl substituted hydrazone MH-2 being the most potent. (IC₅₀ of 0.0896 and 0.1040 µM respectively). The methyl group is responsible for the effective binding to the protein. Thus, a new class of tubulin binding agents have been identified as potential agents in cancer therapy.

Keywords: Anticancer agents; Computational Chemistry; DFT studies; Hydrazones; Molecular docking; β-tubulin.