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首页> 外文期刊>Gene: An International Journal Focusing on Gene Cloning and Gene Structure and Function >Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors
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Design, virtual screening, molecular docking and molecular dynamics studies of novel urushiol derivatives as potential HDAC2 selective inhibitors

机译：新型尿精衍生物作为潜在HDAC2选择性抑制剂的设计，虚拟筛选，分子对接及分子动力学研究

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Abstract Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The binding affinity toward HDAC2 of the compounds was screened by Glide docking. The best scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Six compounds, 21 , 23 , 10 , 19 , 9 and 30 , gave Glide scores of ?7.9 to ?8.5, which revealed that introducing F, Cl, triazole, benzamido, formamido, hydroxyl or nitro substituents onto the benzene ring could increase binding affinity significantly. Molecular docking studies revealed that zinc ion coordination, hydrogen bonding and hydrophobic interactions contributed to the high calculated binding affinities of these compounds toward HDAC2 and that His145, His146, Gly154, Glu103, His183, Asp104, Tyr308 and Phe155 contributed favorably to the binding. MD simulations and binding free energy studies showed that all complexes possessed good stability as characterized by low RMSDs; low RMSFs of residues, moderate hydrogen bonding and zinc ion coordination; and low values of binding free energies. van der Waals and electrostatic interactions provided major contributions to the stability of these complexes. These results show the promising potential of urushiol derivatives as potent HDAC2 binding lead compounds. Graphical abstract Display Omitted Highlights ? 30 novel urushiol derivatives were designed based on FDA-approved HDACI SAHA. ? HDAC2 selective inhibition activities were virtual screened by molecular docking using the grid-based scoring function. ? Six compounds of Glide scores better than SAHA were selected for further molecular docking modes, MD simulations and binding free energy studies. ? The six compounds showed high binding affinities and good stability toward HDAC2.
机译：摘要通过将羟肟酸部分引入烷基侧链的尾部和具有不同电子性质或空间体积的苯环和烷基侧链上的取代基来设计三系列新的脲硫醇衍生物。通过滑动对接筛选化合物的HDAC2的结合亲和力。通过分子对接，MD仿真和结合能量研究进一步加工最佳评分化合物，以分析结合模式和机制。六种化合物，21,23,10,19,9和30，得到了α.7.9至β.8.5的滑动评分，显示出引入F，Cl，三唑，苯甲酰氨基，甲醛，羟基或硝基取代基在苯环上可以增加结合显着的亲和力。分子对接研究表明，锌离子配位，氢键和疏水相互作用导致这些化合物对HDAC2的高计算的结合亲和力，并且他的145，HIS146，G​​LY154，GLU103，HIS183，ASP104，TYR308和PHE155有利地促进到结合。 MD模拟和绑定无能量研究表明，所有复合物都具有良好的稳定性，所述稳定性低于RMSDS的特征;低RMSF的残基，适度氢键和锌离子配位;和粘合能量的低值。 van der Waals和静电相互作用为这些复合物的稳定性提供了主要贡献。这些结果表明毛细血管衍生物作为有效的HDAC2结合铅化合物的有希望的潜力。图形抽象显示省略了亮点？基于FDA批准的HDACI SAHA设计了30个新的尿精衍生物。还HDAC2选择性抑制活性通过使用基于网格的评分功能的分子对接进行虚拟筛选。还选择比萨哈的六种的曲线谱，用于进一步的分子对接模式，MD模拟和结合自由能研究。还该六种化合物显示出高结合亲和力，良好的HDAC2稳定性。

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