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

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Engel CK, Pirard B, Schimanski S, Kirsch R, Habermann J, Klingler O, Schlotte V, Weithmann KU, Wendt KU

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

Chem Biol. 2005 Feb;12(2):181-9.

PubMed ID

15734645 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Polypeptides

Name	UniProt ID
Collagenase 3	P45452	Details

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
PYRIMIDINE-4,6-DICARBOXYLIC ACID BIS-(3-METHYL-BENZYLAMIDE)	Collagenase 3	IC 50 (nM)	72	7.5	22	Details
PYRIMIDINE-4,6-DICARBOXYLIC ACID BIS-(4-FLUORO-3-METHYL-BENZYLAMIDE)	Collagenase 3	IC 50 (nM)	8	7.5	22	Details
PYRIMIDINE-4,6-DICARBOXYLIC ACID BIS-[(PYRIDIN-3-YLMETHYL)-AMIDE]	Collagenase 3	IC 50 (nM)	6600	7.5	22	Details