Matrix metalloproteases: Structure-based drug discovery targets

Abstract

Matrix metalloproteases (MMPs) are a large family of mammalian zinc-dependent proteases that have garnered much attention as targets for drug discovery. In part, this interest is spurred by the central role these enzymes may play in diseases such as arthritis and cancer. One consequence of this attention has been the rapid accumulation of structure information. The structures of inhibitor-MMP complexes have provided a focus for drug discovery efforts in defining features of the MMP catalytic domain that will be critical in developing potent and selective inhibitors. Inhibitor interactions at the active-site zinc are clearly important in defining the binding mode and relative inhibitor potency. Selective inhibitors will also, most likely, take advantage of the S1 substrate binding pocket, as there are relatively obvious differences at this site between the various members of the MMP family.