Seth Cohen and coworkers at University of California San Diego and the Weizmann Institute of Science in Israel designed two libraries based on known zinc chelators: quinoline sulfonamides (QSL) and benzimidazole sulfonamides (BISL) (see Figure). They rapidly assembled 40 of the former and 37 of the later using microwave chemistry and tested these against a handful of different MMPs.
Both libraries produced hits against MMP-2, MMP-3, MMP-8, and MMP-9. Control compounds designed not to chelate zinc showed no activity, and X-ray adsorption fine structure spectroscopy experiments suggest that the molecules are indeed binding to the catalytic zinc. Selectivity is often an issue in targeting metalloproteinases, and it was thus gratifying to find that at least one fragment inhibited MMP-2 with low micromolar activity while showing no activity against the other MMPs. Molecular modeling provides some rationale for this selectivity.
One could argue that many of the library members do not meet conventional definitions of fragments, and could be seen as more scaffold-like (or worse – one has a molecular weight pushing 600 Daltons!) And of course, it is not clear that either scaffold will be suitable for drug development or even tool compounds – it is possible their propensity for zinc binding will be a problem inside cells. Still, the notion of creating custom-made fragment libraries for various classes of targets certainly makes sense; folks have done this for kinases and even RNA, and it is reasonable to see this approach extended to metalloproteinases. Cohen and colleagues described a fragment library consisting of more conventional metal chelators earlier this year in ChemMedChem.
This publication also confirms the results of our poll that fragment-based approaches are catching on in academia. But industry is already in the sandbox: at least two companies, AnCore and Viamet, are using similar strategies to target metalloproteins.
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4 comments:
About the definition of a "Fragment", I think that no one is using the same definition: all the RO3, only MW and logP, MW<300 or 250; 0 or 50 < MW; mix of limit on physicochemical properties with some scaffold selection.... So my question is : In general, which is the definition of a fragment? Only the RO3? I don't think so but .... What is your meaning of that?
You bring up a good point – there isn’t a universally accepted definition for what makes a fragment, though the Rule of 3 is probably the most widely accepted. That said, I think that once molecular weights get above 400 it is hard to call them fragments.
I guess I'm a little disappointed with this paper. OK, a lot disappointed. What, exactly, was the point of taking a known zinc binding motif and doing a fragment screen? It's guaranteed to find something. And something you probably already know (or can guess). Might as well screen a fragment-library of 2-aminopyrimidines against a panel of kinases.
We in industry need to spend more time pushing back the envelope, finding allosteric binders, novel binding modes, fragments that induce conformational changes, etc., etc. But certainly, academia can do better than this. Can't they?
I am with anonymous here. This isn't novel, nor particularly interesting. I think this is a case of Academia "discovering" things that people in industry have known for years, but just can't publish.
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