Exploration of the binding mode between (-)-zampanolide and tubulin using docking and molecular dynamics simulation.
The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin.
Department of Chemistry, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 510182, China, siyanliao@163.com.
Si-Yan
SY
Liao
Guang-Quan
GQ
Mo
Jin-Can
JC
Chen
Kang-Cheng
KC
Zheng
D001665:Binding Sites; D006860:Hydrogen Bonding; D018942:Macrolides / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry
D018942:Macrolides; D014404:Tubulin; C444900:zampanolide