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Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2

Authorized Users Only
2014
Authors
Kalinić, Marko
Zloh, Mire
Erić, Slavica
Article (Published version)
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Abstract
Enhancer of Zeste Homolog 2 (EZH2) is a SET domain protein lysine methyltransferase (PKMT) which has recently emerged as a chemically tractable and therapeutically promising epigenetic target, evidenced by the discovery and characterization of potent and highly selective EZH2 inhibitors. However, no experimental structures of the inhibitors co-crystallized to EZH2 have been resolved, and the structural basis for their activity and selectivity remains unknown. Considering the need to minimize cross-reactivity between prospective PKMT inhibitors, much can be learned from understanding the molecular basis for selective inhibition of EZH2. Thus, to elucidate the binding of small-molecule inhibitors to EZH2, we have developed a model of its fully-formed cofactor binding site and used it to carry out molecular dynamics simulations of protein-ligand complexes, followed by molecular mechanics/generalized born surface area calculations. The obtained results are in good agreement with biochemica...l inhibition data and reflect the structure-activity relationships of known ligands. Our findings suggest that the variable and flexible post-SET domain plays an important role in inhibitor binding, allowing possibly distinct binding modes of inhibitors with only small variations in their structure. Insights from this study present a good basis for design of novel and optimization of existing compounds targeting the cofactor binding site of EZH2.

Keywords:
Enhancer of Zeste Homolog 2 / Epigenetic target / Binding mode elucidation / Molecular dynamics
Source:
Journal of Computer-Aided Molecular Design, 2014, 28, 11, 1109-1128
Publisher:
  • Springer, Dordrecht
Funding / projects:
  • Computational design, synthesis and biological evaluation of new heterocyclic compounds as selective tumorogenesis inhibitors (RS-172009)

DOI: 10.1007/s10822-014-9788-1

ISSN: 0920-654X

PubMed: 25139678

WoS: 000345590000006

Scopus: 2-s2.0-84936760851
[ Google Scholar ]
3
2
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/2140
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
TY  - JOUR
AU  - Kalinić, Marko
AU  - Zloh, Mire
AU  - Erić, Slavica
PY  - 2014
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/2140
AB  - Enhancer of Zeste Homolog 2 (EZH2) is a SET domain protein lysine methyltransferase (PKMT) which has recently emerged as a chemically tractable and therapeutically promising epigenetic target, evidenced by the discovery and characterization of potent and highly selective EZH2 inhibitors. However, no experimental structures of the inhibitors co-crystallized to EZH2 have been resolved, and the structural basis for their activity and selectivity remains unknown. Considering the need to minimize cross-reactivity between prospective PKMT inhibitors, much can be learned from understanding the molecular basis for selective inhibition of EZH2. Thus, to elucidate the binding of small-molecule inhibitors to EZH2, we have developed a model of its fully-formed cofactor binding site and used it to carry out molecular dynamics simulations of protein-ligand complexes, followed by molecular mechanics/generalized born surface area calculations. The obtained results are in good agreement with biochemical inhibition data and reflect the structure-activity relationships of known ligands. Our findings suggest that the variable and flexible post-SET domain plays an important role in inhibitor binding, allowing possibly distinct binding modes of inhibitors with only small variations in their structure. Insights from this study present a good basis for design of novel and optimization of existing compounds targeting the cofactor binding site of EZH2.
PB  - Springer, Dordrecht
T2  - Journal of Computer-Aided Molecular Design
T1  - Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2
VL  - 28
IS  - 11
SP  - 1109
EP  - 1128
DO  - 10.1007/s10822-014-9788-1
ER  - 
@article{
author = "Kalinić, Marko and Zloh, Mire and Erić, Slavica",
year = "2014",
abstract = "Enhancer of Zeste Homolog 2 (EZH2) is a SET domain protein lysine methyltransferase (PKMT) which has recently emerged as a chemically tractable and therapeutically promising epigenetic target, evidenced by the discovery and characterization of potent and highly selective EZH2 inhibitors. However, no experimental structures of the inhibitors co-crystallized to EZH2 have been resolved, and the structural basis for their activity and selectivity remains unknown. Considering the need to minimize cross-reactivity between prospective PKMT inhibitors, much can be learned from understanding the molecular basis for selective inhibition of EZH2. Thus, to elucidate the binding of small-molecule inhibitors to EZH2, we have developed a model of its fully-formed cofactor binding site and used it to carry out molecular dynamics simulations of protein-ligand complexes, followed by molecular mechanics/generalized born surface area calculations. The obtained results are in good agreement with biochemical inhibition data and reflect the structure-activity relationships of known ligands. Our findings suggest that the variable and flexible post-SET domain plays an important role in inhibitor binding, allowing possibly distinct binding modes of inhibitors with only small variations in their structure. Insights from this study present a good basis for design of novel and optimization of existing compounds targeting the cofactor binding site of EZH2.",
publisher = "Springer, Dordrecht",
journal = "Journal of Computer-Aided Molecular Design",
title = "Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2",
volume = "28",
number = "11",
pages = "1109-1128",
doi = "10.1007/s10822-014-9788-1"
}
Kalinić, M., Zloh, M.,& Erić, S.. (2014). Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2. in Journal of Computer-Aided Molecular Design
Springer, Dordrecht., 28(11), 1109-1128.
https://doi.org/10.1007/s10822-014-9788-1
Kalinić M, Zloh M, Erić S. Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2. in Journal of Computer-Aided Molecular Design. 2014;28(11):1109-1128.
doi:10.1007/s10822-014-9788-1 .
Kalinić, Marko, Zloh, Mire, Erić, Slavica, "Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2" in Journal of Computer-Aided Molecular Design, 28, no. 11 (2014):1109-1128,
https://doi.org/10.1007/s10822-014-9788-1 . .

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