The crystal structure of FED1 shows a binding mode similar to EPZ004777, with the tert-butyl phenyl urea motif further extending the binding pocket compared to SAM.
Overall, these data support the initial hypothesis that the [Y]-AII superior selectivity to AT2R is based on a more hydrophobic and compact binding pocket (compared to AT1R).
However, Nutlin-3 cannot bind to MDMX, most likely due to the presence of various sequence differences in its p53-binding pocket compared to MDM2 [27], [27].
Neonicotinoids with an electronegative pharmacophore are embraced by a reversed position in the binding pocket compared with a nicotinoid cationic functionality.
Zebrafish PXR showed the most constrained pharmacophore based on the 16 ligands, suggesting a small binding pocket compared with the other PXRs, consisting of 3 hydrophobes, 1 hydrogen bond acceptor, and excluded volumes.
An interesting feature of the TPT molecule concerns the mobility of the di-methyl-amino group on the A ring, that is altered in the enzyme-DNA binding pocket, as compared to the simulation of TPT in water solution [24].
In part, this may be due to the relatively closed conformation of the binding pocket when compared to crystal structures of related PWWP domains bound to methylated peptides (Additional file 1: Figure S2c).
The 19F NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening.
The peptide backbone for residues 441 445 moves inward, and thus the entrance size of aldehyde-binding pocket decreases, compared to that of wild-type enzyme (Figure S12C), which might explain the decreased Km and the increased specificity toward 3-HPA.
