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June 19, 2014
Speaking of Polyphenols. . .
Yesterday's mention of "nightmare polyphenols" prompted a reader to ask about the one in this paper. That's it over there at the left, and yeah, that sure is a polyphenol. In fact, it's a chaetochromin, a family of mycotoxins originally isolated from moldy rice. The paper doesn't say anything about its stereochemistry, but some can be inferred from their docking models.
Their compound, denoted 4548-G05, does seem to stimulate the insulin receptor, and the list of things that do that is not a long one. A small-molecule IR compound could be quite useful in diabetes patients, of course, but no one's every been able to come up with a plausible drug candidate. Merck made a big splash back in 1999 with another fungal metabolite, L-783,281, but that never became a drug, either. This new paper advances a hypothesis of where the polyphenol binds to the extracellular domain of the insulin receptor and how it might exert its actions.
I would wonder, though, if this compound can't do the same membrane tricks as the other polyphenols mentioned yesterday. The chaetochromins seem to have a number of biological effects, which could be through all sorts of mechanisms. There's nothing to say that some of them aren't due to direct ligand-binding interactions (such as the one proposed in this latest paper), but I wouldn't rule out membrane perturbations, either. And I wouldn't bet on 4058-G05 becoming a drug, although it might lead to one eventually, after a lot of hard work.
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