Structural determinants of affinity and selectivity in the binding of inhibitors to histone deacetylase 6

Bioorg Med Chem Lett. 2020 Apr 15;30(8):127023. doi: 10.1016/j.bmcl.2020.127023. Epub 2020 Feb 11.

Abstract

Histone deacetylase 6 (HDAC6) is associated with multiple neurological disorders as well as aggressive cancers, making its selective inhibition highly desirable for therapeutic purposes. The basic molecular design of an effective HDAC6 inhibitor consists of a zinc-binding group, a linker, and a capping group capable of making interactions at the mouth of the active site. To date, more than 50 high-resolution X-ray crystal structures of HDAC6-inhibitor complexes have been reported, many of which reveal intermolecular interactions that contribute to isozyme affinity and selectivity. Here, we review the key features of HDAC6 inhibitor design illuminated by these structural studies.

Keywords: Enzyme; Inhibitor; X-ray crystallography.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase 6 / metabolism
  • Histone Deacetylase Inhibitors / chemical synthesis
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Zebrafish
  • Zebrafish Proteins / antagonists & inhibitors*
  • Zebrafish Proteins / metabolism

Substances

  • Histone Deacetylase Inhibitors
  • Zebrafish Proteins
  • HDAC6 protein, human
  • HDAC6 protein, zebrafish
  • Histone Deacetylase 6