title: 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 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000, Belgrade, Serbia.
authors.forename: Marko
authors.initials: M
authors.lastname: Kalinić
authors.forename: Mire
authors.initials: M
authors.lastname: Zloh
authors.forename: Slavica
authors.initials: S
authors.lastname: Erić
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D000071221:Enhancer of Zeste Homolog 2 Protein; D044127:Epigenesis, Genetic; D006657:Histones / Q000737:chemistry*; D006801:Humans; D056004:Molecular Dynamics Simulation; D063151:Polycomb Repressive Complex 2 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D006657:Histones; D054852:Small Molecule Libraries; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2