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Matrix metalloproteinases (MMPs) cleave and degrade most components of the extracellular matrix, and unregulated MMP activity has been correlated to cancer and metastasis. Hence there is a burgeoning need to develop inhibitors that bind selectively to structurally similar MMPs. The inhibition profiles of peptidomimetics containing C α  substituents at the α,β unsaturated carbon were evaluated against the recombinant forms of ADAM17, MMP1, and MMP9. The dicarboxylic acid  D2  and hydroxamate  C2  inhibited MMP9 but not MMP1. The unsaturated compound  E2  displayed selective inhibition for MMP1, compared with the saturated precursor  C2 , with an IC 50  value of 3.91 μ m . The molecular basis for this selectivity was further investigated by the molecular docking of  E2  and  D2  into the active sites of MMP1 and MMP9. These data demonstrate hydrogen-bonding interactions between the carbonyl group of the C α  substituent of  E2  and the side chain of Asn180 present in the active site of MMP1. Conversely, the docked MMP9- D2  structure shows hydrophobic and hydrogen bonding between the ligand’s morpholine substituent and second carboxylic acid group with Leu187 and an amide, respectively. This study suggests that substituents other than P 1 ′ and P 2 ′ may confer selectivity among MMPs and may aid in the search for novel lead compounds.

The significance of the C α substituent in the selective inhibition of matrix metalloproteinases 1 and 9