Park, Insun Hwang, Yu Jin Kim, TaeHun Viswanath, Ambily Nath Indu Londhe, Ashwini M. Jung, Seo Yun Sim, Kyoung Mi Min, Sun-Joon Lee, Ji Eun Seong, Jihye Kim, Yun Kyung No, Kyoung Tai Ryu, Hoon Pae, Ae Nim 2024-01-20T00:31:51Z 2024-01-20T00:31:51Z 2021-09-05 2017-10 0920-654X https://pubs.kist.re.kr/handle/201004/122237 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. English SPRINGER CHROMATIN-STRUCTURE METHYLTRANSFERASE ESET HETEROCHROMATIN G9A EXPRESSION INHIBITOR ALIGNMENT GENE In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level Article 10.1007/s10822-017-0052-3 1 JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, v.31, no.10, pp.877 - 889 JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN 31 10 877 889 scie scopus 000413448900002 2-s2.0-85028886867 Biochemistry & Molecular Biology Biophysics Computer Science, Interdisciplinary Applications Biochemistry & Molecular Biology Biophysics Computer Science Article CHROMATIN-STRUCTURE METHYLTRANSFERASE ESET HETEROCHROMATIN G9A EXPRESSION INHIBITOR ALIGNMENT GENE SETDB1/ESET Huntington&apos s disease Pharmacophore Homology modeling Virtual screening Trimethylated H3K9 (H3K9me3) Peptide-competitive small molecule inhibitors