title: Seeking for Non-Zinc-Binding MMP-2 Inhibitors: Synthesis, Biological Evaluation and Molecular Modelling Studies.
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.
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. alessandra.ammazzalorso@unich.it.
authors: Alessandra
authors: A
authors: Ammazzalorso
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. barbara.defilippis@unich.it.
authors: Barbara
authors: B
authors: De Filippis
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. cristina.campestre@unich.it.
authors: Cristina
authors: C
authors: Campestre
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università "A. Moro" Bari, Via Orabona 4, 70125 Bari, Italy. antonio.laghezza@uniba.it.
authors: Antonio
authors: A
authors: Laghezza
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. alessandro.marrone@unich.it.
authors: Alessandro
authors: A
authors: Marrone
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. rosa.amoroso@unich.it.
authors: Rosa
authors: R
authors: Amoroso
authors: Dipartimento di Farmacia-Scienze del Farmaco, Università "A. Moro" Bari, Via Orabona 4, 70125 Bari, Italy. paolo.tortorella@uniba.it.
authors: Paolo
authors: P
authors: Tortorella
authors: Dipartimento di Farmacia, Università "G. d'Annunzio" Chieti, Via dei Vestini 31, 66100 Chieti, Italy. m.agamennone@unich.it.
authors: Mariangela
authors: M
authors: Agamennone
mesh_terms: D015195:Drug Design; D057075:Enzyme Assays; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009287:Naphthyridines / Q000138:chemical synthesis / Q000737:chemistry*; D011485:Protein Binding; D000072417:Protein Domains; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D015032:Zinc / Q000737:chemistry
chemical_list: D006912:Hydroxyquinolines; D061965:Matrix Metalloproteinase Inhibitors; D009287:Naphthyridines; D011994:Recombinant Proteins; D020778:Matrix Metalloproteinase 2; D015032:Zinc
keywords: MMPs; docking; inhibitors; isoquinoline; molecular dynamics; non-zinc-binding group; quinoline; ureas