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

doi:10.1016/j.bmcl.2019.08.002

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

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2581-2586. doi: 10.1016/j.bmcl.2019.08.002. Epub 2019 Aug 2.

Authors

Lydia Daniel¹, Michael P Gotsbacher¹, Tomas Richardson-Sanchez¹, William Tieu¹, Rachel Codd²

Affiliations

¹ School of Medical Sciences (Pharmacology), The University of Sydney, New South Wales 2006, Australia.
² School of Medical Sciences (Pharmacology), The University of Sydney, New South Wales 2006, Australia. Electronic address: rachel.codd@sydney.edu.au.

PMID: 31400937
DOI: 10.1016/j.bmcl.2019.08.002

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.

Keywords: Histone deacetylases (HDACs); Homology modelling; Hydroxamic acids; Molecular modelling; N-Hydroxycinnamamide.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cinnamates / chemistry
Cinnamates / pharmacology*
Dose-Response Relationship, Drug
Histone Deacetylase 1 / antagonists & inhibitors*
Histone Deacetylase 1 / metabolism
Histone Deacetylase 2 / antagonists & inhibitors*
Histone Deacetylase 2 / metabolism
Histone Deacetylase Inhibitors / chemical synthesis
Histone Deacetylase Inhibitors / chemistry
Histone Deacetylase Inhibitors / pharmacology*
Humans
Hydroxamic Acids / chemical synthesis
Hydroxamic Acids / chemistry
Hydroxamic Acids / pharmacology*
Models, Molecular
Molecular Structure
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Structure-Activity Relationship

Substances

Cinnamates
Histone Deacetylase Inhibitors
Hydroxamic Acids
Small Molecule Libraries
HDAC1 protein, human
HDAC2 protein, human
Histone Deacetylase 1
Histone Deacetylase 2
cinnamamide