title: Synthesis, experimental evaluation and molecular modelling of hydroxamate derivatives as zinc metalloproteinase inhibitors.
abstract: Enzymes of the M4 family of zinc-metalloproteinases are virulence factors secreted from gram-positive or gram-negative bacteria, and putative drug targets in the treatment of bacterial infections. In order to have a therapeutic value such inhibitors should not interfere with endogenous zinc-metalloproteinases. In the present study we have synthesised a series of hydroxamate derivatives and validated the compounds as inhibitors of the M4 enzymes thermolysin and pseudolysin, and the endogenous metalloproteinases ADAM-17, MMP-2 and MMP-9 using experimental binding studies and molecular modelling. In general, the compounds are stronger inhibitors of the MMPs than of the M4 enzymes, however, an interesting exception is LM2. The compounds bound stronger to pseudolysin than to thermolysin, and the molecular modelling studies showed that occupation of the S2(') subpocket by an aromatic group is favourable for strong interactions with pseudolysin.
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Stian
authors.initials: S
authors.lastname: Sjøli
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Nuti
authors.affiliation: Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Caterina
authors.initials: C
authors.lastname: Camodeca
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Irina
authors.initials: I
authors.lastname: Bilto
authors.affiliation: Dipartimento di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Armando
authors.initials: A
authors.lastname: Rossello
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Jan-Olof
authors.initials: JO
authors.lastname: Winberg
authors.affiliation: Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway. Electronic address: Ingebrigt.Sylte@uit.no.
authors.forename: Ingebrigt
authors.initials: I
authors.lastname: Sylte
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Olayiwola A
authors.initials: OA
authors.lastname: Adekoya
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000072198:ADAM17 Protein; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013820:Thermolysin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D051722:ADAM Proteins; D020778:Matrix Metalloproteinase 2; D013820:Thermolysin; D020780:Matrix Metalloproteinase 9; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: Adamalysins; Bacterial virulence factors; Docking and scoring; Enzyme selective inhibition; M4 family; Matrix metalloproteinases; Molecular dynamics simulations; Zinc-metalloproteinases