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EMBL Chemical Biology: Substrate Activity Screening

The day starts off with Jonathan Ellman talking about substrate activity screening, a very interesting technique that builds on optimized artificial enzyme substrates and turns them into inhibitors. He’s published a number of papers on this, and it looks like his current efforts are targeting phosphatases. I wish him luck with that; those have been a very tough field to work in. He also seems to be looking at some of the epigenetic enzymes, and I look forward to seeing how that comes out as well.
I asked him a question at the end of his talk, since I couldn’t help but notice that many of his SAR compounds rely on hydrophobic interactions to get potency. His phosphatase inhibitors featured things like a ring with two CF3 groups and a bromine, or another aryl with a cyclohexyl on it, all of which are getting pretty greasy. He replied that they have been able to find some enthalpic interactions (particularly when targeting Cathepsin S), but that they have the same problems as everyone else in finding good polar interactions as opposed to getting potency through grease.