Abstract
Matrix metalloproteinases (MMPs) are an important family of zinc-containing enzymes with a central role in many physiological and pathological processes. Although several MMP inhibitors have been synthesized over the years, none reached the market because of off-target effects, due to the presence of a zinc binding group in the inhibitor structure. To overcome this problem non-zinc-binding inhibitors (NZIs) have been recently designed. In a previous article, a virtual screening campaign identified some hydroxynaphtyridine and hydroxyquinoline as MMP-2 non-zinc-binding inhibitors. In the present work, simplified analogues of previously-identified hits have been synthesized and tested in enzyme inhibition assays. Docking and molecular dynamics studies were carried out to rationalize the activity data.
Highlights
Matrix metalloproteinases are calcium and zinc-containing proteases (24 in humans) involved in the hydrolysis of the extracellular matrix (ECM) components and, responsible for tissue remodeling in physiological conditions [1]
It has been demonstrated that Matrix metalloproteinases (MMPs) involvement in several diseases can be due to the hydrolysis of substrates other than ECM components, in particular chemokines involved in inflammation and immune response [1,12]
Ever since the first ligands had been disclosed almost 30 years ago, several MMP inhibitors (MMPIs) have been discovered, but none reached the market because of relevant side effects emerging in long-term treatment (musculoskeletal syndrome (MSS)) [13]
Summary
Matrix metalloproteinases are calcium and zinc-containing proteases (24 in humans) involved in the hydrolysis of the extracellular matrix (ECM) components and, responsible for tissue remodeling in physiological conditions [1]. It has been demonstrated that MMP involvement in several diseases can be due to the hydrolysis of substrates other than ECM components, in particular chemokines involved in inflammation and immune response [1,12]. Traditional MMPIs are constituted by a functional group binding the zinc ion (zinc binding group (ZBG)) and chemical functions mimicking the substrate and interacting with the MMP subsites, in particular with the hydrophobic S1’ site. The ZBG is represented in most of the cases by the hydroxamate function, that binds very efficiently in the MMP active site, but can possibly bind other divalent cations and cause an unselective inhibition of other metallo-enzymes
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