A Comparison of the Binding Sites of Matrix Metalloproteinases and Tumor Necrosis Factor-α Converting Enzyme: Implications for Selectivity

MMPs and TACE (ADAM-17) assume independent, parallel, or opposite pathological roles in
cancer, arthritis, and several other diseases. For therapeutic purposes, selective inhibition of
individual MMPs and TACE is required in most cases due to distinct roles in diseases and the
need to preserve activities in normal states. Toward this goal, we compared force-field
interaction energies of five ubiquitous inhibitor atoms with flexible binding sites of 24 known
human MMPs and TACE. The results indicate that MMPs 1−3, 10, 11, 13, 16, and 17 have at
least one subsite very similar to TACE. S3 subsite is the best target for development of specific
TACE inhibitors. Specific binding to TACE compared to most MMPs is promoted by placing a
negatively charged ligand part at the bottom of S2 subsite, at the entrance of S1‘ subsite, or
the part of S3‘ subsite that is close to catalytic zinc. Numerous other clues, consistent with
available experimental data, are provided for design of selective inhibitors.