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Merck

Structural basis for the highly selective inhibition of MMP-13.

Chemistry & biology (2005-03-01)
Christian K Engel, Bernard Pirard, Sandra Schimanski, Reinhard Kirsch, Jörg Habermann, Otmar Klingler, Volkhard Schlotte, Klaus Ulrich Weithmann, K Ulrich Wendt
ABSTRACT

Inhibitors for matrix metalloproteinases (MMPs) are under investigation for the treatment of cancer, arthritis, and cardiovascular disease. Here, we report a class of highly selective MMP-13 inhibitors (pyrimidine dicarboxamides) that exhibit no detectable activity against other MMPs. The high-resolution X-ray structures of three molecules of this series bound to MMP-13 reveal a novel binding mode characterized by the absence of interactions between the inhibitors and the catalytic zinc. The inhibitors bind in the S1' pocket and extend into an additional S1' side pocket, which is unique to MMP-13. We analyze the determinants for selectivity and describe the rational design of improved compounds with low nanomolar affinity.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
MMP-13 Inhibitor, The MMP-13 Inhibitor, also referenced under CAS 544678-85-5, controls the biological activity of MMP-13. This small molecule/inhibitor is primarily used for Protease Inhibitors applications.
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