2. Academic Validation
  3. Exploring hydroxamic acid inhibitors of HDAC1 and HDAC2 using small molecule tools and molecular or homology modelling

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.
Lydia Daniel 1,  Michael P Gotsbacher 1,  Tomas Richardson-Sanchez 1,  William Tieu 1,  Rachel Codd 2
Affiliations

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.

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