Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations
Exploration of the valproic acid binding site on histone deacetylase 8 using docking and molecular dynamic simulations
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DOI：
10.1007/s00894-011-1240-z
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发表时间：
2012-06-01
影响因子：
2.2
通讯作者：
Correa-Basurto, Jose
中科院分区：
文献类型：
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作者：
Antonio Bermudez-Lugo, Jorge;Perez-Gonzalez, Oscar;Correa-Basurto, Jose
表观遗传学疗法是癌症治疗药物开发研究的重要焦点。丙戊酸（VPA）是一种HDAC抑制剂，已在临床研究中进行了评价。尽管它在治疗癌症方面取得了成功，但HDAC中VPA的抑制机制尚不清楚。为此，我们使用对接和分子动力学模拟研究VPA结合HDAC，采用本地和重建的3-D结构。结果表明，VPA通过羧基与HDAC催化位点（CS）上的Zn原子及其他局部残基（H141-142和Y360）发生配位作用。这导致静电和氢键相互作用，同时与疏水侧链几乎没有相互作用，导致低亲和力。然而，在对不同的天然HDAC 3-D结构进行几次对接研究并使用MD模拟的几个快照后，很明显VPA在位于乙酰释放通道（称为疏水活性位点通道（HASC））的位点处具有最高亲和力。VPA对HASC的亲和力是由于其高度疏水性，使得VPA能够参与与Y18、I19、Y20、V25、R37、A38、V41、H42、I135和W137的货车范德华相互作用，而VPA的羧酸酯基团与S138、I19、N136和W137的主链具有几种氢键相互作用。分子动力学模拟结果表明，HASC门的不断打开和关闭影响VPA对HASC的亲和力，但VPA对HASC的亲和力始终高于CS，表明HASC可能参与了VPA的抑制机制。
Epigenetic therapy is an important focus of research for drug development in the treatment of cancer. Valproic acid (VPA) is an HDAC inhibitor that has been evaluated in clinical studies. Despite its success in treating cancer, the mechanism of inhibition of VPA in HDAC is unknown. To this end, we have used docking and molecular dynamic simulations to investigate VPA binding to HDAC, employing both native and rebuilt 3-D structures. The results showed that VPA, via its carboxyl group, coordinates the Zn atom and other local residues (H141-142 and Y360) located at the catalytic site (CS) of HDAC. This causes electrostatic and hydrogen bonding interactions while having little interaction with the hydrophobic side chains, resulting in a low affinity. However, after several docking studies on different native HDAC 3-D structures and after using several snapshots from MD simulations, it became apparent that VPA bound with highest affinity at a site located at the acetyl-releasing channel, termed the hydrophobic active site channel (HASC). The affinity of VPA for HASC was due to its highly hydrophobic properties that allow VPA to take part in van der Waals interactions with Y18, I19, Y20, V25, R37, A38, V41, H42, I135 and W137, while VPA's carboxylate group has several hydrogen bonding interactions with the backbones of S138, I19, N136 and W137. MD simulations showed that the HASC door continuously opened and closed, which affected the affinity of VPA to the HASC, but the affinity toward the HASC was consistently higher than that obtained for the CS, suggesting that the HASC could be involved in the mechanism of inhibition.