title: The significance of the C(α) substituent in the selective inhibition of matrix metalloproteinases 1 and 9.
abstract: 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 μm. 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.
authors.affiliation: Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Observatory 7925, Cape Town, South Africa.
authors.forename: Riyad
authors.initials: R
authors.lastname: Domingo
authors.forename: Kelly
authors.initials: K
authors.lastname: Chibale
authors.forename: Edward D
authors.initials: ED
authors.lastname: Sturrock
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000737:chemistry / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D057786:Peptidomimetics / Q000737:chemistry* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D057786:Peptidomimetics; D011480:Protease Inhibitors; D051722:ADAM Proteins; D020780:Matrix Metalloproteinase 9; D020781:Matrix Metalloproteinase 1; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse