Journal of Computer-Aided Molecular Design

, Volume 28, Issue 11, pp 1109–1128 | Cite as

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



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.


Enhancer of Zeste Homolog 2 Epigenetic target Binding mode elucidation Molecular dynamics 



This work was funded by the Ministry of Education and Science of the Republic of Serbia through Project Number 172009. Results presented in this work were obtained using the computational resources of the PARADOX cluster at the Scientific Computing Laboratory of the Institute of Physics Belgrade, Serbia, as part of the High-Performance Computing Infrastructure for South East Europe’s Research Communities (HP-SEE). HP-SEE is a project co-funded by the European Commission (under Contract Number 261499) through the Seventh Framework Programme ( The authors gratefully acknowledge Dr. Jelena Ranđelović (University of Belgrade—Faculty of Pharmacy, Department of Organic Chemistry) for insightful discussions and technical assistance.

Supplementary material

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Supplementary material 1 (DOC 8945 kb)


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Faculty of PharmacyUniversity of BelgradeBelgradeSerbia
  2. 2.Department of PharmacyUniversity of HertfordshireHatfieldUK

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