Chemical probe for DNA-repair enzyme MTH1
The fragment was identified by merging two hits obtained from docking a library of aspartic protease inhibitors in the binding site of MTH1. Further hit optimization was guided by molecular dynamics simulations. Ligand design was then validated by crystallography (PDB code 6EQ7).
The aspartate residues 119 and 120 establish hydrogen bonds, in a similar fashion as the analogous residues in the aspartic protease BACE1. The phenylalanine 27 is involved in an edge-to-face (T-shaped) interaction with the 3-fluoro-pyridine of the fragment.
To visualize the ligand (in magenta) and the residues Phe27, Asp119 and Asp120, copy the following script into the corresponding box and hit "Apply":
ZOOM IN ;
select chain=A ; trace ; wireframe off ;
select resno=27, 119, 120 ; wireframe 0.2 ;
select hetero ; wireframe 0.2 ;
select carbon and hetero ; color magenta ;
center {hetero} ;