Do biological activities of selective histone deacetylase 6 (HDAC6) inhibitors rely on the modification of cap group?

Abstract

Nowadays, significant progress has been made in the development of selective histone deacetylase 6 (HDAC6) inhibitors, exerting great potential in the treatment of various malignant tumors and neurodegenerative diseases. Previously, selective inhibitory activities of HDAC inhibitors were generally considered sensitive to the interactions between the Cap group and the binding site of HDAC6, and a large number of selective HDAC6 inhibitors have been designed and synthesized based on the strategy. However, some inhibitors without Cap group could also exhibit excellent potency and selective inhibition towards HDAC6, and in this study, BRD9757 and compound 8, as capless selective HDAC6 inhibitors, were selected as molecular probes to explore the difference of their binding interactions in HDAC1&6. Through the analysis of binding‐free energies and conformational rearrangements after 1 μs molecular dynamics simulation, it could be learned that although the residues in the binding site remained highly consistent, the binding mechanisms of BRD9757 and compound 8 in HDAC1&6 were different, which will provide valuable hints for the discovery of novel selective HDAC6 inhibitors.

Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1H-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation

“…Thus, the design and synthesis of selective HDAC6 inhibitors have received widespread attention. − Selective HDAC6 inhibitors satisfied the classic pharmacophore model and are mainly composed of three parts: (1) the cap group (Cap) that occupies the rim region of a catalytic pocket; (2) the linker moiety (Linker) interacting with the residues in the hydrophobic pocket; (3) zinc binding group (ZBG) chelating with the zinc ion (Zn 2+ ) locating at the bottom of the pocket (Figure ). Based on the in-depth analysis of characteristics of the HDAC6 active pocket, the residues located on the rim of the active pocket were nonconservative, and the channel appeared wider and shallower than that of the HDAC1 subtype. − Therefore, the interactions between the Cap and the key residues in the active pocket affected the binding conformations and target affinity of the compounds, thereby causing the compounds to produce a certain degree of subtype-selective inhibitory activities.…”