25 March 2015

We read these papers so you don't have to

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).  
Table 1. 
The key compound is 7, with 25 microM IC50;  while 6 (minus the methyl ester) is 1000x less potent.  Strange things are afoot at the Circle K.  They then docked 7 (and a few other "second tier" compounds).  They see "moderate" binding for all compounds; yet, one of these compounds is more than 50x more potent than the others.  We've been down this road before...


Anonymous said...

I am suprised you even bothered reading anything from that journal.....last time I checked (maybe five years ago) it was full of crap. seems that it still is.

perhaps a fundamental misunderstanding on your part - this work was not published to advance science in any really meaningful way, but probably to provide a PhD student with a publication.

Dr. Teddy Z said...

I try not to have Publicational Bias...but, yes I tend to agree here.