title: Probing the S1' site for the identification of non-zinc-binding MMP-2 inhibitors.
abstract: Matrix metalloproteinases (MMPs) are zinc-dependent enzymes involved in several pathological states. Among them, MMP-2 is a relevant therapeutic target because of its role in cancer development and progression. Many MMP inhibitors (MMPIs) have been discovered over the last 30 years, and the majority of them contain a functional group that binds the zinc ion (zinc-binding group; ZBG). Unfortunately, no MMPIs have reached the market yet, owing to toxic effects due to unselective interactions of the ZBG. The new generation of MMPIs that do not bind the zinc ion could overcome problems of selectivity and toxicity, but have so far been developed only for MMP-8, -12, and -13. In this work, a virtual screening protocol was established by combining ligand- and structure-based methods to identify non-zinc-binding MMP-2 inhibitors using a new-generation MMP-8 inhibitor as a probe to find unexplored interactions in the MMP-2 S1' site. The screening allowed the identification of micromolar MMP-2 inhibitors that putatively avoid binding the zinc ion, as demonstrated by docking calculations. The LIA model, built to correlate predicted and experimental binding energies of the identified non-zinc-binding MMP-2 hits, underpins the reliability of the predicted docking poses.
authors.affiliation: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66013 Chieti, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Di Pizio
authors.forename: Antonio
authors.initials: A
authors.lastname: Laghezza
authors.forename: Paolo
authors.initials: P
authors.lastname: Tortorella
authors.forename: Mariangela
authors.initials: M
authors.lastname: Agamennone
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D007700:Kinetics; D008024:Ligands; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry* / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry / Q000378:metabolism
chemical_list: D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D020033:Protein Isoforms; D020778:Matrix Metalloproteinase 2; D015032:Zinc
keywords: inhibitors; matrix metalloproteinases; metalloenzymes; non-zinc binding; virtual screening