SOLUTION STRUCTURES OF STROMELYSIN COMPLEXED TO THIADIAZOLE INHIBITORS

Unregulated or overexpressed matrix metalloproteinases (MMPs), includi ng stromelysin, collagenase, and gelatinase, have been implicated in s everal pathological conditions including arthritis and cancer. Small-m olecule MMP inhibitors may have therapeutic value in the treatment of these diseases. In this regard, the solution structures of two stromel ysin/inhibitor complexes have been investigated using H-1, C-13, and N -15 NMR spectroscopy. Both inhibitors are members of a novel class of matrix metalloproteinase inhibitor that contain a thiadiazole soup and that interact with stromelysin in a manner distinct from other classe s of inhibitors. The inhibitors coordinate the catalytic zinc atom thr ough their exocyclic sulfur atom, with the remainder of the ligand ext ending into the S-1-S-3 side of the active site. The binding of inhibi tor containing a protonated or fluorinated aromatic ring was investiga ted using H-1 and F-19 NMR spectroscopy. The fluorinated ring was foun d to have a reduced ring-flip rate compared to the protonated version. A strong, coplanar interaction between the fluorinated ring of the in hibitor and the aromatic ring of Tyr155 is proposed to account for the reduced ring-flip rate and for the increase in binding affinity obser ved for the fluorinated inhibitor compared to the protonated inhibitor . Binding interactions observed for the thiadiazole class of Ligands h ave implications for the design of matrix metalloproteinase inhibitors .