A comparative study based on docking and molecular dynamics simulations over HDAC-tubulin dual inhibitors.

基于对接和分子动力学模拟的 HDAC - 微管蛋白双重抑制剂的比较研究。

• 影响指数: 2.942
• 发表时间: 11 2016
• 来源期刊: J Mol Graph Model
• DOI: 10.1016/j.jmgm.2016.10.007
• PMID: 27750186
• 文章类型: Comparative Study
• 作者列表: Hassanzadeh M,Bagherzadeh K,Amanlou M

关键词: Docking; Free binding energy; Histone deacetylase 1; Histone deacetylase 8; Hybrid ligands; Molecular dynamics simulations

Mesh: Amino Acids / chemistry; Catalytic Domain; Histone Deacetylase Inhibitors / chemistry; Histone Deacetylases / chemistry; Inhibitory Concentration 50; Ions; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Reproducibility of Results; Thermodynamics; Tubulin / chemistry; Tubulin Modulators / chemistry; Zinc / chemistry

Abstract

Nowadays the ability to prediction of complex behavior rationally based on the computational approaches has been a successful technique in drug discovery. In the present study interactions of a new series of hybrids, which were made by linking colchicine as a tubulin inhibitor and suberoylanilide hydroxamic acid (SAHA) as a HDAC inhibitor, with HDAC8 and HDAC1 were investigated and compared. This research has been facilitated by the availability of experimental information besides employing docking methodology as well as classical molecular dynamics simulations and binding free energy calculation were performed. The obtained findings indicate different modes of interactions and inhibition strengths of the studied inhibitors for HDAC8 and HDAC1. HDAC8 binding free energies (-34.35 to -26.27kcal/mol) revealed higher binding affinity to HDAC8 compared to HDAC1 (-33.17 to -7.99kcal/mol). The binding energy contribution of each residue with the hybrid compounds 4a-4e within the active site of HDAC1 and HDAC8 was analyzed and the results confirmed the rule of key amino acids in interaction with the hybrid compounds.

摘要

如今，基于计算方法合理预测复杂行为的能力已成为药物发现的成功技术。在本研究中，一系列新的杂种的相互作用，通过连接秋水仙碱作为微管蛋白抑制剂和辛二酰苯胺异羟肟酸（SAHA）作为HDAC抑制剂，与HDAC8和HDAC1进行了调查和比较。除了采用对接方法以及经典的分子动力学模拟和结合自由能计算外，实验信息的可用性也促进了这项研究。获得的发现表明所研究的HDAC8和HDAC1抑制剂的相互作用模式和抑制强度不同。与HDAC1（-33.17至-7.99kcal/mol）相比，HDAC8结合自由能（-34.35至-26.27kcal/mol）显示出对HDAC8更高的结合亲和力。分析了HDAC1和HDAC8活性位点内每个残基与杂化化合物4a-4e的结合能贡献，结果证实了关键氨基酸与杂化化合物相互作用的规律。