The high structural homology of histone deacetylases 6 and 8 (HDAC6/8) poses a challenge in achieving isoform selectivity and has resulted in adverse side effects due to pan-inhibition in clinical applications. Additionally, the rational design of dual-target inhibitors, centered on HDAC6/8, demands a profound understanding of their selectivity mechanisms. Addressing the urgent need for enhanced specificity in the development of inhibitors targeting specific isoforms, we elucidate the mechanism underpinning the selective inhibition of HDAC6/8 inhibitors through in-silico strategies. The hydrogen bonding interaction with Asp101 and Tyr306 is a key factor that enables compound 12b to selectively inhibit HDAC8. Its favorable spatial orientation places the Cap group of 12b between Tyr306 and Tyr100, resulting in an overall L-shaped conformation. These two factors significantly contribute to the selective inhibitory activity of 12b against HDAC8. The zinc binding group (ZBG) of compound NN-390 forms a hydrogen bond with His610, a key residue of HDAC6, facilitating stable chelation with zinc ions. In addition, the Cap group of NN-390 interacts with Phe620 and Phe680 via van der Waals forces, leading to an overall Y-shaped conformation. The aforementioned factors are the main reasons for the selective inhibition of HDAC6 by NN-390. Furthermore, whether the Cap group is in the para or meta-position will influence the selective inhibition of either HDAC6 or HDAC8. We believe these clues can offer valuable insights for the rational design of selective inhibitors targeting HDAC6/8 and pave the way for rational design of dual-target HDAC6/8-based inhibitors.Communicated by Ramaswamy H. Sarma.

中文翻译：

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综合分子建模和动力学方法揭示了 HDAC6/8 选择性抑制的机制。


组蛋白脱乙酰酶 6 和 8 （HDAC6/8） 的高结构同源性对实现亚型选择性构成了挑战，并且在临床应用中由于泛抑制而导致不良副作用。此外，以 HDAC6/8 为中心的双靶点抑制剂的合理设计需要对其选择性机制有深刻的理解。为了满足在开发靶向特定亚型的抑制剂时对增强特异性的迫切需求，我们阐明了通过计算机模拟策略支持 HDAC6/8 抑制剂选择性抑制的机制。与 Asp101 和 Tyr306 的氢键相互作用是使化合物 12b 选择性抑制 HDAC8 的关键因素。其有利的空间方向将 12b 的 Cap 基团置于 Tyr306 和 Tyr100 之间，从而产生整体的 L 形构象。这两个因素显着促进了 12b 对 HDAC8 的选择性抑制活性。化合物 NN-390 的锌结合基团 （ZBG） 与 HDAC6 的关键残基 His610 形成氢键，促进与锌离子的稳定螯合。此外，NN-390 的 Cap 基团通过范德华力与 Phe620 和 Phe680 相互作用，导致整体 Y 形构象。上述因素是 NN-390 选择性抑制 HDAC6 的主要原因。此外，Cap 组是否处于 para 或 meta 位置将影响 HDAC6 或 HDAC8 的选择性抑制。我们相信这些线索可以为靶向 HDAC6/8 的选择性抑制剂的合理设计提供有价值的见解，并为基于双靶点 HDAC6/8 的抑制剂的合理设计铺平道路。由 Ramaswamy H. Sarma 传达。