15 September 2014

A COMT Tease...

S-adenosyl-methionine (SAM) is a hot molecule; you could probably make a good living selling it these days.  SAM-transferases of all types are "hot" targets, especially in epigenetics.  However, one current target is COMT, or catechol-O-methyl transferase.  COMT lives in a far different space than the epigenetics one, neurodegeneration.  There are several current Parkinson's Disease treatments based upon catechol, but as you would expect, there is toxicity associated with these.  
So, a team at Takeda decided to go after SAM-competitive molecules.  To this end, they screened 11,000 fragments using a enzymatic assay @100 uM.  52 hits (>15% inhibition) were found for a 0.15% hit rate.  They note this is a very low hit rate for what appears to be a very ligandable pocket. They then used LC-MS/MS and SPR to remove reactive moieties and non-SAM competitive molecules.  This led to compounds (4-6) and SAR by Corporate Collection (7). 
They followed up on these four compounds with DSF, STD-NMR, and X-ray.  They were able to co-crystallize 5 with mouse COMT.  This is the first (reported) structure of COMT with a SAM-competitive molecule. 

They mention that they took a "build up" approach, but I presume that is for for future papers. 

1 comment:

Dan Erlanson said...

This is a nice paper, though the researchers note strong interspecies differences in affinities, which may complicate animal studies down the road.