Glycogen Phosphorylase is one of those systems that you hear about all the time; it was the first allosteric enzyme discovered. It's been discussed here and here previously on this blog. It is one of those ubiquitous enzymes and has been the subjet of a lot of research looking for allosteric modulators. The majority of allosteric inhibitors are heterocyclic compounds with a well known history. This paper wants to add to that history.
The authors start with what appears to be a dreadful understanding of what fragment-based hit generation is.
"Lead-like discovery refers to the screening of low molecular weight libraries with detection of weak affinities in the high micromolar to millimolar range".
Maybe its just me, but we've been over this before. Lead-like molecules, as Kubinyi showed, are large and decorated; fragments are not. So, they got the low molecular weight thing right, but the name of the method wrong. Maybe an error in the proofing...Starting on previous work, the chose a 21 member heterocycle library (Figure 1.) to investigate a morpholine-based peptide mimetic.
|Figure 1. Fragment Library|
Activity was determined by an enzymatic assay with a maximal compound concentration of 222mM. They also used 22mM, 56 mM, 111mM leading to Table 1 and some crazy SAR (N-Boc-ing 8 yielded 9 with >200x potency).