Insight into the structural determinants for selective inhibition of matrix metalloproteinases

The matrix metalloproteinase (MMP) family has been a pharmaceutical target for over 20 years. Despite massive research and development efforts, only one MMP inhibitor (Periostat) has been approved by the FDA for the treatment of periodontal disease. Possible reasons for the low success rate of MMP inhibitors in the clinic include unwanted side effects caused by their lack of selectivity, poor oral bioavailability and decreased potency in vivo. We review how three-dimensional structures (3D) of MMP inhibitor complexes as well as the inhibition profile of compounds screened on MMP can be used to guide the optimization of selectivity of MMP inhibitors. Analysis of MMP 3D structures provides a ranking of their pockets on the basis of opportunities for selective interactions. One can use inhibition data to build pharmacophore or quantitative structure–activity models (QSAR) for virtual screening of libraries of novel MMP inhibitors. Combining protein- and ligand-based approaches, we conclude that targeting a single pocket is not always sufficient to achieve the desired selectivity profile. Finally, we also outline novel series of selective MMP inhibitors that exploit differences in the intrinsic flexibility of the catalytic domain to form selective interactions with a given MMP.