Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2
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 dynamicsSource:
Journal of Computer-Aided Molecular Design, 2014, 28, 11, 1109-1128Publisher:
- Springer, Dordrecht
Funding / projects:
- Computational design, synthesis and biological evaluation of new heterocyclic compounds as selective tumorogenesis inhibitors (RS-MESTD-Basic Research (BR or ON)-172009)
DOI: 10.1007/s10822-014-9788-1
ISSN: 0920-654X
PubMed: 25139678
WoS: 000345590000006
Scopus: 2-s2.0-84936760851
Collections
Institution/Community
PharmacyTY - 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 . .