Identification of New Potential Microtubule Stabilizers via Virtual Screen, Biological Evaluation, and Molecular Dynamics Simulation

ABSTRACT Microtubules have become an attractive target for human cancer treatment. Several microtubule stabilizers targeting for taxane site have been widely employed for various tumor treatments in clinic. In this study, to discover novel scaffolds of microtubule stabilizers targeting the taxane site, pharmacophore modeling, molecular docking, and naive Bayes classification models were developed and further applied to screen database with 29,158 compounds. Forty agents were filtered out and considered as potential microtubule stabilizers. The MTT assay showed that hit20 exhibited higher antiproliferative activity against H1299 cell, the IC 50 value of which was 16.8 μM. The hit20 conspicuously promoted tubulin polymerization in vitro, and disrupted the intracellular microtubule network of H1299 cells. Moreover, the hit20 caused cells to accumulate at G2/M phase, induced cell apoptosis, and significantly inhibited H1299 cell migration. The results of the molecular dynamics simulation revealed that tubulin‐hit20 could form a stable complex, inducing the H6‐H7 loop and M‐loop regions produce greater fluctuation. The Δ G bind of tubulin‐hit20 was—130.77 kJ/mol, and −156.3 kJ/mol for the tubulin‐paclitaxel. In summary, the hit20 is a promising microtubule stabilizer targeting the taxane site and should be further investigated for the development of a novel antitumor agent.