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) 是目前在临床实践中用于治疗癫痫以及双相情感障碍和情绪障碍的化合物。VPA 靶向组蛋白去乙酰化酶 (HDAC)，它参与从几种蛋白质中的赖氨酸中去除乙酰基，调节生物体内的多种功能。这些酶的失衡或故障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 仅针对 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 方式的结构和能量信息。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。发现 VPA 到达 HDAC1-3 和 7 中的催化位点，而在 HDAC6 中，VPA 仅到达催化隧道。在 HDAC4 中，VPA 与 L1 和 L2 相邻，L1 和 L2 是参与抑制因子结合的区域，而在 HDAC8 中，VPA 与疏水活性位点通道 (HASC) 结合，与之前的报道一致。