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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综合分子模型和动力学方法揭示了 HDAC6/8 的选择性抑制机制。

组蛋白脱乙酰酶 6 和 8 (HDAC6/8) 的高度结构同源性对实现异构体选择性提出了挑战，并因临床应用中的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的深刻理解。为了满足开发针对特定异构体的抑制剂增强特异性的迫切需求，我们通过计算机策略阐明了 HDAC6/8 抑制剂选择性抑制的机制。与 Asp101 和 Tyr306 的氢键相互作用是化合物 12b 能够选择性抑制 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，从而形成整体 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，形成整体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基团处于对位还是间位都会影响HDAC6或HDAC8的选择性抑制。我们相信这些线索可以为合理设计针对 HDAC6/8 的选择性抑制剂提供有价值的见解，并为合理设计基于 HDAC6/8 的双靶点抑制剂铺平道路。Ramaswamy H. Sarma 通讯。