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May 10, 2010
Here's a new paper from the folks at the Burnham Institute and UCSD on a new target for vaccinia virus. They're going after a virulence factor (N1L) through computational screening, which is a challenge, since this is a protein-protein interaction.
They pulled out a number of structures, which have some modest activity in cell infection assays. In addition, they showed through calorimetry that the compounds do appear to be affecting the target protein, specifically its equilibrium between monomeric and oligomeric forms. But the structures of their best hits. . .well, here's the table. You can ignore compounds 6 and 8; they show up as cytotoxic. But the whole list is pretty ghastly, at least to my eyes.
These sorts of highly aromatic polyphenol structures have two long traditions in medicinal chemistry: showing activity in assays, for the first part, and not being realizable as actual drugs, for the second. There's no doubt that they can do a lot of things; it's just that getting them to do them in a real-world situation is not trivial. Part of the problem is specificity (and associated toxicity) and part of it is pharmacokinetics. As you'd imagine, these compounds can have rather funky clearance behavior, what with all those phenols.
So I'd regard these as proof-of-concept compounds that validate N1L as a target. I think that we'll need to wait for someone to format up an assay for high-throughput (non-virtual) screening to see if something more tractable comes up. Either that, or rework the virtual screens on the basis that we've seen enough polyphenols come up on this target already. . .
Note: readers of the paper will note that our old friend resveratrol turns up as an active compound as well. It's very much in the polyphenol tradition; make of that what you will.
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