Laboratorio de Modelado Molecular, Bioinformática y Diseño de Fármacos de La Escuela Superior de Medicina, Instituto Politécnico Nacional, México, Plan de San Luis Y Diaz Mirón S/N, Col. Casco de Santo Tomas, CP: 11340, Mexico City, Mexico.
J Comput Aided Mol Des. 2020 Aug;34(8):857-878. doi: 10.1007/s10822-020-00304-2. Epub 2020 Mar 16.
Valproic acid (VPA) is a compound currently used in clinical practice for the treatment of epilepsy as well as bipolar and mood disorders. VPA targets histone deacetylases (HDACs), which participate in the removal of acetyl groups from lysine in several proteins, regulating a wide variety of functions within the organism. An imbalance or malfunction of these enzymes is associated with the development and progression of several diseases, such as cancer and neurodegenerative diseases. HDACs are divided into four classes, but VPA only targets Class I (HDAC1-3 and 8) and Class IIa (HDAC4-5, 7 and 9) HDACs; however, structural and energetic information regarding the manner by which VPA inhibits these HDACs is lacking. Here, the structural and energetic features that determine this recognition were studied using molecular docking and molecular dynamics (MD) simulation. It was found that VPA reaches the catalytic site in HDAC1-3 and 7, whereas in HDAC6, VPA only reaches the catalytic tunnel. In HDAC4, VPA was bound adjacent to L1 and L2, a zone that participates in corepressor binding, and in HDAC8, VPA was bound to the hydrophobic active site channel (HASC), in line with previous reports.
丙戊酸（VPA）是一种目前在临床实践中用于治疗癫痫以及双相和情绪障碍的化合物。VPA 靶向组蛋白去乙酰化酶（HDACs），其参与从几种蛋白质的赖氨酸上去除乙酰基，调节生物体中的多种功能。这些酶的不平衡或功能障碍与多种疾病的发展和进展有关，例如癌症和神经退行性疾病。HDAC 分为四类，但 VPA 仅靶向 I 类（HDAC1-3 和 8）和 IIa 类（HDAC4-5、7 和 9）HDAC；然而，缺乏关于 VPA 抑制这些 HDAC 的方式的结构和能量信息。在这里，使用分子对接和分子动力学（MD）模拟研究了决定这种识别的结构和能量特征。结果发现，VPA 到达 HDAC1-3 和 7 的催化位点，而在 HDAC6 中，VPA 仅到达催化隧道。在 HDAC4 中，VPA 结合到 L1 和 L2 附近，该区域参与核心抑制剂结合，在 HDAC8 中，VPA 结合到疏水性活性位点通道（HASC），与先前的报告一致。
