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Identification of Molecular Interactions within Histone Deacetylase Isozymes for the Development of Selective HDAC2 Inhibitors for the Design of Targeted Cancer Therapies
Author(s) -
May Xavier,
Watkins Davita,
Stoddard Shana V.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.921.20
Subject(s) - histone deacetylase , vorinostat , histone deacetylase 2 , docking (animal) , histone , chemistry , histone deacetylase 5 , isozyme , cancer research , in silico , computational biology , biology , pharmacology , gene , biochemistry , medicine , enzyme , nursing
Histone deacetylase inhibitors (HDACi) are necessary for the therapeutic intervention of various cancers. HDACi decrease the function of a class of isozymes called histone deacetylases (HDAC). HDAC's are involved in the regulation of gene expression. Various members of this HDAC family are being targeted for therapeutic design. HDAC2 is seen to have elevated levels of expression with colorectal cancer. Our two part docking study compared our nine potential synthetic targets and known HDACi's Belinostat, Mocetinostat, Vorinostat, and Panobinostat within 11 HDAC isozymes to determine which candidates would be the best for synthesis. Additionally, we looked to determine if there are any molecular interactions that can be taken advantage of for the design of a more selective HDACi. ETS4 shows promising signs of in silico selectivity. HDAC2 and HDAC11 both experience binding score values that are 100 times higher than the other receptors. We observed pi‐pi stacking interaction with F155 and F 210 within the core of the receptor, as well as metal ion coordination and multiple hydrogen bonds throughout the receptor for HDAC2. Interestingly, HDAC11 does not have this pi‐pi stacking interaction occur, yet still has a high binding score. The work from this study will help to develop more selective HDAC2 inhibitors for targeted cancer therapies. Support or Funding Information William Randolph Hearst Foundation and Rhodes College Department of Chemistry