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. Author manuscript; available in PMC: 2021 Mar 1.
Published in final edited form as: Eur J Med Chem. 2020 Jan 2;189:112023. doi: 10.1016/j.ejmech.2019.112023

Figure 5. DOT1L modeling with 9 and complex structure with EPZ004777.

Figure 5.

Protein carbons are colored gray, ligand carbons are colored green, all other atoms by atom type (O red, N blue, S yellow, H white). Interactions are indicated with dashed lines. (A) Co-crystal structure of EPZ004777 in complex with DOT1L (PDB code 4ER5). EPZ004777 head-group region forms hydrogen bonds with D222, F223(backbone) and K187 (backbone). In the linker region, the diol forms bidentate hydrogen bonding interactions with E186, the protonated tertiary nitrogen forms inductive interactions with Y128, and both nitrogens of the urea form hydrogen bonds to D161. Lastly, the tert-butylbenzene of the tail group region forms non-polar (not shown) and aromatic hydrogen bonding interactions. (B) Docked pose of 9. The tail group region maintains non-polar interactions similar to EPZ004777. In the linker region, the triazole forms strong pi-pi interactions with Y128, the oxygen of the carbonyl forms hydrogen bonding interactions with N241. 9 head group region forms hydrogen bonding interaction with G163 (backbone) and, in contrast to EPZ004777, forms hydrogen bonding interactions E129 and orients to form aromatic hydrogen bonding interactions with N241.