Integrated molecular modeling and dynamics approaches revealed the mechanism of selective inhibition of HDAC6/8

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 <i>in-silico</i> strategies. The hydrogen bonding interaction with Asp101 and Tyr306 is a key factor that enables compound <b>12b</b> to selectively inhibit HDAC8. Its favorable spatial orientation places the Cap group of <b>12b</b> between Tyr306 and Tyr100, resulting in an overall L-shaped conformation. These two factors significantly contribute to the selective inhibitory activity of <b>12b</b> against HDAC8. The zinc binding group (ZBG) of compound <b>NN-390</b> forms a hydrogen bond with His610, a key residue of HDAC6, facilitating stable chelation with zinc ions. In addition, the Cap group of <b>NN-390</b> interacts with Phe620 and Phe680 <i>via</i> 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 <b>NN-390</b>. 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