Exploring hydroxamic acid inhibitors of HDAC1 and HDAC2 using small molecule tools and molecular or homology modelling

Lydia Daniel, Michael P. Gotsbacher, Tomas Richardson-Sanchez, William Tieu, Rachel Codd

Research output: Contribution to journalArticlepeer-review

Abstract

Hydroxamic acid compounds 1–10 containing a N-hydroxycinnamamide scaffold and a 4-(benzylamino)methyl cap group that was either unsubstituted (1) or substituted with one (2–4) or two (5–10) methoxy groups in variable positions were prepared as inhibitors of Zn(II)-containing histone deacetylases (HDACs). The 3,4- (9) and 3,5- (10) bis-methoxy-substituted compounds were the least potent against HeLa nuclear extract, HDAC1 and HDAC2. Molecular modelling showed methoxy groups in the 3-, 4- and 5-position, but not the 2-position, had unfavourable steric interactions with the G32-H33-P34 triad on a loop at the surface of the HDAC2 active site cavity. An HDAC1 homology model showed potential ionic (E243.K288) and cation-pi (K247.F292) interactions between helix 10 and helix 11 that were absent in HDAC2 ((G243.K288) and (K247.V292)). This surface-located interhelical constraint could inform the design of bitopic HDAC1 and HDAC2 selective ligands using an allosteric approach, and/or protein-protein interaction (PPI) inhibitors.

Original languageEnglish
Pages (from-to)2581-2586
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume29
Issue number18
Early online date2 Aug 2019
DOIs
Publication statusPublished or Issued - 15 Sep 2019
Externally publishedYes

Keywords

  • Histone deacetylases (HDACs)
  • Homology modelling
  • Hydroxamic acids
  • Molecular modelling
  • N-Hydroxycinnamamide

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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