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J Comput Aided Mol Des. 2017 Oct;31(10):877-889. doi: 10.1007/s10822-017-0052-3. Epub 2017 Sep 6.

In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level.

Author information

1
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
2
Department of Biotechnology, Yonsei University, Seoul, 03722, Republic of Korea.
3
Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea.
4
Department of Integrated Biomedical and Life Science, Korea University, Seoul, 02841, Republic of Korea.
5
Department of Applied Chemistry, Hanyang University, Ansan, Gyeonggi-do, 15888, Republic of Korea.
6
Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea.
7
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea. hoonryu@bu.edu.
8
Department of Neurology and Boston University Alzheimer's Disease Center, Boston University School of Medicine, Boston, MA, 02118, USA. hoonryu@bu.edu.
9
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology, Seoul, 02792, Republic of Korea. anpae@kist.re.kr.
10
Division of Bio-Medical Science &Technology, KIST School, Korea University of Science and Technology, Daejeon, 34113, Republic of Korea. anpae@kist.re.kr.

Abstract

ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are reported to correlate with Huntington's disease (HD) progression and mood-related disorders which make SETDB1/ESET a viable drug target. In this context, the present investigation was performed to identify novel peptide-competitive small molecule inhibitors of the SETDB1/ESET by a combined in silico-in vitro approach. A ligand-based pharmacophore model was built and employed for the virtual screening of ChemDiv and Asinex database. Also, a human SETDB1/ESET homology model was constructed to supplement the data further. Biological evaluation of the selected 21 candidates singled out 5 compounds exhibiting a notable reduction of the H3K9me3 level via inhibitory potential of SETDB1/ESET activity in SETDB1/ESET-inducible cell line and HD striatal cells. Later on, we identified two compounds as final hits that appear to have neuronal effects without cytotoxicity based on the result from MTT assay. These compounds hold the calibre to become the future lead compounds and can provide structural insights into more SETDB1/ESET-focused drug discovery research. Moreover, these SETDB1/ESET inhibitors may be applicable for the preclinical study to ameliorate neurodegenerative disorders via epigenetic regulation.

KEYWORDS:

Homology modeling; Huntington’s disease; Peptide-competitive small molecule inhibitors; Pharmacophore; SETDB1/ESET; Trimethylated H3K9 (H3K9me3); Virtual screening

PMID:
28879500
DOI:
10.1007/s10822-017-0052-3
[Indexed for MEDLINE]

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