Wangzaozin A, a potent novel microtubule stabilizer, targets both the taxane and laulimalide sites on β-tubulin through molecular dynamics simulations.

Wangzaozin A, an ent-kaurene diterpenoid isolated from Isodon racemosa (Hemsl) Hara, promotes the polymerization of intracellular microtubules as well as purified tubulin, which is similar to other known microtubule stabilizers. Our pharmacological results showed that wangzaozin A induced G2/M cell cycle arrest and the significant inhibition of cancer cell proliferation. A molecular docking study indicated that wangzaozin A could bind to both the taxane and laulimalide (lau) sites on β-tubulin, which is a novel binding mode that differs from that of known microtubule stabilizers. Furthermore, molecular dynamics simulation and binding free energy calculations demonstrated that wangzaozin A could stably bind to taxane and lau sites simultaneously and form a double-bonded complex. The binding mode of wangzaozin A to the taxane site was more similar to that of epothilone A than paclitaxel. Our results demonstrate that wangzaozin A represents a novel class of microtubule stabilizers, and may serve as a potential microtubule-targeting lead compound for further structural optimization.