Small molecular exogenous modulators of active forms of MMPs

Matrix metalloproteinases (MMPs) are endopeptidases, and their activity depends on calcium and zinc metal ions. These enzymes are expressed originally in zymogenic form, where the active site of proteins is closed by a prodomain which is removed during activation. A homeostatic balance of their activity is primarily regulated by a ‘cysteine switch’ located on a consensus sequence of the prodomain and natural endogenous inhibitors, called tissue inhibitors of metalloproteinases (TIMPs). Breakage of this homeostasis may lead to various pathological conditions, which may require further activation and/or inhibition of these enzymes to regenerate that balance. Here, we report four modulators, more specifically, three inhibitors (I1, I2 and I3), and one exogenous activator (L) of the active form of human collagenase MMP-1 (without prodomain). The results were confirmed by binding studies using fluorescence-based enzyme assays. [Display omitted] •Four exogenous modulators to active forms of MMPs are reported.•Three molecules are determined to be regular competitive inhibitors and one novel activator to MMPs.•The binding of one of the reported inhibitors became weaker towards MMP-1 in the presence of the reported activator.•Docking Studies indicate inhibitors bind within the active site pocket.•Allosteric pocket for binding of activator is determined closer to omega loop connecting α2 and α3 helices.