X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: Implications for inhibitor selectivity

Effective inhibitors of matrix metalloproteinases (MMPs), a family of conne ctive tissue-degrading enzymes, could be useful for the treatment of diseas es such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discov ered nonpeptidic MMP inhibitors with improved properties, and report here t he crystal structures of human stromelysin-l catalytic domain (SCD) complex ed with four of these inhibitors. The structures were deter mined and refin ed at resolutions ranging from 1.64 to 2.0 Angstrom. Each inhibitor binds i n the active site of SCD such that a bulky diphenyl piperidine moiety penet rates a deep, predominantly hydrophobic S-1' pocket. The active site struct ure of the SCD is similar in all four inhibitor complexes, but differs subs tantially from the peptide hydroxamate complex, which has a smaller side ch ain bound in the S-1' pocket. The largest differences occur in the loop for ming the "top" of this pocket. The occupation of these nonpeptidic inhibito rs in the Si pocket provides a structural basis to explain their selectivit y among MMPs. An analysis of the unique binding mode predicts structural mo difications to design improved MMP inhibitors.