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