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

Insun Park, Yu Jin Hwang, Tae Hun Kim, Ambily Nath Indu Viswanath, Ashwini M. Londhe, Seo Yun Jung, Kyoung Mi Sim, Sun Joon Min, Ji Eun Lee, Jihye Seong, Yun Kyung Kim, Kyoung Tai No, Hoon Ryu, Ae Nim Pae

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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. Graphical Abstract: [Figure not available: see fulltext.].

Original languageEnglish
Pages (from-to)877-889
Number of pages13
JournalJournal of Computer-Aided Molecular Design
Volume31
Issue number10
DOIs
Publication statusPublished - 2017 Oct 1

Fingerprint

lysine
Huntington Disease
Epigenomics
Computer Simulation
Histones
inhibitors
Histone-Lysine N-Methyltransferase
drugs
moods
disorders
Lead compounds
lead compounds
Corpus Striatum
Heterochromatin
evaluation
homology
supplements
Gene Silencing
Drug Discovery
Cytotoxicity

All Science Journal Classification (ASJC) codes

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

Cite this

Park, Insun ; Hwang, Yu Jin ; Kim, Tae Hun ; 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. / In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level. In: Journal of Computer-Aided Molecular Design. 2017 ; Vol. 31, No. 10. pp. 877-889.
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title = "In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level",
abstract = "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. Graphical Abstract: [Figure not available: see fulltext.].",
author = "Insun Park and Hwang, {Yu Jin} and Kim, {Tae Hun} and Viswanath, {Ambily Nath Indu} and Londhe, {Ashwini M.} and Jung, {Seo Yun} and Sim, {Kyoung Mi} and Min, {Sun Joon} and Lee, {Ji Eun} and Jihye Seong and Kim, {Yun Kyung} and No, {Kyoung Tai} and Hoon Ryu and Pae, {Ae Nim}",
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Park, I, Hwang, YJ, Kim, TH, Viswanath, ANI, Londhe, AM, Jung, SY, Sim, KM, Min, SJ, Lee, JE, Seong, J, Kim, YK, No, KT, Ryu, H & Pae, AN 2017, 'In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level', Journal of Computer-Aided Molecular Design, vol. 31, no. 10, pp. 877-889. https://doi.org/10.1007/s10822-017-0052-3

In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level. / Park, Insun; Hwang, Yu Jin; Kim, Tae Hun; 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.

In: Journal of Computer-Aided Molecular Design, Vol. 31, No. 10, 01.10.2017, p. 877-889.

Research output: Contribution to journalArticle

TY - JOUR

T1 - In silico probing and biological evaluation of SETDB1/ESET-targeted novel compounds that reduce tri-methylated histone H3K9 (H3K9me3) level

AU - Park, Insun

AU - Hwang, Yu Jin

AU - Kim, Tae Hun

AU - Viswanath, Ambily Nath Indu

AU - Londhe, Ashwini M.

AU - Jung, Seo Yun

AU - Sim, Kyoung Mi

AU - Min, Sun Joon

AU - Lee, Ji Eun

AU - Seong, Jihye

AU - Kim, Yun Kyung

AU - No, Kyoung Tai

AU - Ryu, Hoon

AU - Pae, Ae Nim

PY - 2017/10/1

Y1 - 2017/10/1

N2 - 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. Graphical Abstract: [Figure not available: see fulltext.].

AB - 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. Graphical Abstract: [Figure not available: see fulltext.].

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M3 - Article

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