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Design In Silico, Synthesis and Binding Evaluation of a Carbohydrate‐Based Scaffold for Structurally Novel Inhibitors of Matrix Metalloproteinases

The matrix metalloproteinases (MMPs) are members of a continuously growing family of Zn-dependent endopeptidases that function extracellularly. This clan of enzymes, specialized in endopeptidase activity, is involved in both normal and pathological tissue remodeling. Activation and over-expression of MMPs seem to be connected with pathological conditions such as arthritis, cardiovascular diseases, multiple sclerosis, and cancer-cell metastasis. Since preclinical studies clearly showed that the inhibition of MMPs would be therapeutic for such diseases, the generation of effective and selective inhibitors has become an extremely attractive goal. Early approaches to the identification of potential MMP inhibitors (i.e. substrate-based design of peptidomimetics and random screening of natural product or compound libraries) have recently been replaced by structure–activity relationship (SAR) studies. Deeper insights into enzyme–ligand interactions have been possible from SAR studies, and structure elucidation through X-ray and NMR spectroscopy of MMP catalytic domain/inhibitor complexes showed that the interaction of the inhibitor with zinc in the active site is very important in determining biological potency. Beside the active-site zinc(ii) ion, all MMPs are characterized by a hydrophobic cavity, conventionally designated the S1’ pocket, which offers the greatest opportunity for selective-inhibitor design because there is considerable variation between the MMPs in its dimensions and the residues that line the pocket. Thus peptidomimetics that incorporate a zinc ligand and S1’ side chain represent one of the most common classes of MMP inhibitors (i.e. Marimastat, Batimastat), while another class of zinc ligand compounds are sulfonamide-based inhibitors such as NNGH or AG3340.