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dc.creatorKalinić, Marko
dc.creatorZloh, Mire
dc.creatorErić, Slavica
dc.date.accessioned2019-09-02T11:40:03Z
dc.date.available2019-09-02T11:40:03Z
dc.date.issued2014
dc.identifier.issn0920-654X
dc.identifier.urihttp://farfar.pharmacy.bg.ac.rs/handle/123456789/2140
dc.description.abstractEnhancer 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.publisherSpringer, Dordrecht
dc.relationinfo:eu-repo/grantAgreement/MESTD/Basic Research (BR or ON)/172009/RS//
dc.rightsrestrictedAccess
dc.sourceJournal of Computer-Aided Molecular Design
dc.subjectEnhancer of Zeste Homolog 2en
dc.subjectEpigenetic targeten
dc.subjectBinding mode elucidationen
dc.subjectMolecular dynamicsen
dc.titleStructural insights into binding of small molecule inhibitors to Enhancer of Zeste Homolog 2en
dc.typearticle
dc.rights.licenseARR
dcterms.abstractЕрић, Славица; Калинић, Марко; Злох, Мире;
dc.citation.volume28
dc.citation.issue11
dc.citation.spage1109
dc.citation.epage1128
dc.citation.other28(11): 1109-1128
dc.citation.rankM21
dc.identifier.wos000345590000006
dc.identifier.doi10.1007/s10822-014-9788-1
dc.identifier.pmid25139678
dc.identifier.scopus2-s2.0-84936760851
dc.identifier.rcubconv_3208
dc.type.versionpublishedVersion


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