Characterization of an exosite binding inhibitor of matrix metalloproteinase 13.
Matrix metalloproteinase 13 (MMP13) is a key enzyme implicated in the degradation of the extracellular matrix in osteoarthritis. Clinical administration of broad spectrum MMP inhibitors such as marimastat has been implicated in severe musculo-skeletal side effects. Consequently, research has been focused on designing inhibitors that selectively inhibit MMP13, thereby circumventing musculo-skeletal toxicities. A series of pyrimidine dicarboxamides were recently shown to be highly selective inhibitors of MMP13 with a novel binding mode. We have applied a molecular ruler to this exosite by dual inhibition studies involving a potent dicarboxamide in the presence of two metal chelators of different sizes. A larger hydroxamate mimic overlaps and antagonizes binding of the dicarboxamide to the exosite whereas the much smaller acetohydroxamate synergizes with the dicarboxamide. These studies elucidate the steric requirement for compounds that fit exclusively into the active site, a mandate for generating highly selective MMP13 inhibitors.
Department of Enzymology and Mechanistic Pharmacology, GlaxoSmithKline Pharmaceuticals, Collegeville, Pennsylvania 19426, USA. gooljat@wyeth.com
Lata T
LT
Gooljarsingh
Ami
A
Lakdawala
Frank
F
Coppo
Lusong
L
Luo
Gregg B
GB
Fields
Peter J
PJ
Tummino
Richard R
RR
Gontarek
D001665:Binding Sites; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D053509:Matrix Metalloproteinase 13 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D008958:Models, Molecular; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D019714:Tissue Inhibitor of Metalloproteinases / Q000737:chemistry* / Q000494:pharmacology
D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D053509:Matrix Metalloproteinase 13