Prikaz osnovnih podataka o dokumentu
Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2
dc.creator | Kalinić, Marko | |
dc.creator | Zloh, Mire | |
dc.creator | Erić, Slavica | |
dc.date.accessioned | 2019-09-02T11:40:03Z | |
dc.date.available | 2019-09-02T11:40:03Z | |
dc.date.issued | 2014 | |
dc.identifier.issn | 0920-654X | |
dc.identifier.uri | https://farfar.pharmacy.bg.ac.rs/handle/123456789/2140 | |
dc.description.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. | en |
dc.publisher | Springer, Dordrecht | |
dc.relation | info:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172009/RS// | |
dc.rights | restrictedAccess | |
dc.source | Journal of Computer-Aided Molecular Design | |
dc.subject | Enhancer of Zeste Homolog 2 | en |
dc.subject | Epigenetic target | en |
dc.subject | Binding mode elucidation | en |
dc.subject | Molecular dynamics | en |
dc.title | Structural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2 | en |
dc.type | article | |
dc.rights.license | ARR | |
dcterms.abstract | Ерић, Славица; Калинић, Марко; Злох, Мире; | |
dc.citation.volume | 28 | |
dc.citation.issue | 11 | |
dc.citation.spage | 1109 | |
dc.citation.epage | 1128 | |
dc.citation.other | 28(11): 1109-1128 | |
dc.citation.rank | M21 | |
dc.identifier.wos | 000345590000006 | |
dc.identifier.doi | 10.1007/s10822-014-9788-1 | |
dc.identifier.pmid | 25139678 | |
dc.identifier.scopus | 2-s2.0-84936760851 | |
dc.type.version | publishedVersion |