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June 25, 2014
Where's the Widest Variety of Chemical Matter?
A look through some of the medicinal chemistry literature this morning got me to thinking: does anyone have any idea of which drug target has the most different/diverse chemical matter that's been reported against it? I realize that different scaffolds are in the eye of the beholder, so it's going to be impossible to come up with any exact counts. But I think that all the sulfonamides that hit carbonic anhydrase, for example, should for this purpose be lumped together: that interaction with the zinc is crucial, and everything else follows after. Non-sulfonamide CA inhibitors would each form a new class for each new zinc-interacting motif, and any compounds that don't hit the zinc at all (are there any?) would add to the list, too. Then you have allosteric compounds, which are necessarily going to look different than active-site inhibitors.
My guess is that some of the nuclear receptors would turn out to win this competition. They can have large, flexible binding pockets that seem to recognize a variety of chemotypes. So maybe this question should be divided up a bit more:
1. What enzyme is known to have the widest chemical variety of active-site inhibitors?
2. Which GPCR has the widest chemical variety of agonists? Antagonists? (The antagonists are going to win this one, surely).
3. And the the open field question asked above: what drug target of any kind has had the widest variety of molecules reported to act on it, in any fashion?
I don't imagine that we'll come to any definitive answer to any of these, but some people may have interesting nominations.
Update: in response to a query in the comments, maybe we should exempt the drug-metabolizing enzymes from the competition, since their whole reason for living is to take on a wide variety of unknown chemical structures.
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