Structural basis for the highly selective inhibition of MMP-13.
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.
Engel
Christian K
CK
Aventis Pharma Deutschland GmbH, A Company of the Sanofi-Aventis Group, Industrial Park Hoechst, D-65926 Frankfurt, Germany.
Pirard
Bernard
B
Schimanski
Sandra
S
Kirsch
Reinhard
R
Habermann
Jörg
J
Klingler
Otmar
O
Schlotte
Volkhard
V
Weithmann
Klaus Ulrich
KU
Wendt
K Ulrich
KU
D000595:Amino Acid Sequence; D001665:Binding Sites; D017364:Collagenases / Q000737:chemistry*; D018360:Crystallography, X-Ray; D015195:Drug Design; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D014867:Water
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D014867:Water; D017364:Collagenases; D053509:Matrix Metalloproteinase 13