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Publication Abstract from PubMed

After the disappointment of clinical trials with early broad spectrum synthetic inhibitors of matrix metalloproteinases (MMPs), the field is now resurging with a new focus on the development of selective inhibitors that fully discriminate between different members of the MMP family with several therapeutic applications in perspective. Here, we report a novel class of highly selective MMP-12 inhibitors, without a phosphinic zinc-binding group, designed to plunge deeper into the S(1)' cavity of the enzyme. The best inhibitor from this series, identified through a systematic chemical exploration, displays nanomolar potency toward MMP-12 and selectivity factors that range between 2 and 4 orders of magnitude toward a large set of MMPs. Comparison of the high resolution x-ray structures of MMP-12 in free state or bound to this new MMP-12 selective inhibitor reveals that this compound fits deeply within the S(1)' specificity cavity, maximizing surface/volume ratios, without perturbing the S(1)' loop conformation. This is in contrast with highly selective MMP-13 inhibitors that were shown to select a particular S(1)' loop conformation. The search for such compounds that fit precisely to preponderant S(1)' loop conformation of a particular MMP may prove to be an alternative effective strategy for developing selective inhibitors of MMPs.

Insights from selective non-phosphinic inhibitors of MMP-12 tailored to fit with an S1' loop canonical conformation.,Devel L, Garcia S, Czarny B, Beau F, LaJeunesse E, Vera L, Georgiadis D, Stura E, Dive V J Biol Chem. 2010 Nov 12;285(46):35900-9. Epub 2010 Sep 3. PMID:20817735^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.