title: Inhibition of pseudolysin and thermolysin by hydroxamate-based MMP inhibitors.
abstract: In the present study, we have investigated the inhibition of thermolysin and pseudolysin by a series of compounds previously identified as matrix metalloproteinase (MMP) inhibitors using experimental binding studies and theoretical calculations. The experimental studies showed that some of the compounds were able to inhibit thermolysin and pseudolysin in the low μM range. The studies revealed that, in general, the compounds bound in the order MMPs > pseudolysin > thermolysin, and the strongest pseudolysin and thermolysin binders were compounds 8-12. Furthermore, compounds 8 and 9 were unique in that they bound much stronger to the two bacterial enzymes than to the MMPs. The docking calculations suggested that the phenyl group of the strongest binders (compounds 8 and 9) occupy the S2(')-subpocket, while a second ring system occupy the S1-subpocket in both thermolysin and pseudolysin. When the compounds possess two ring systems, the largest and most electron rich ring system seems to occupy the S1-subpocket.
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037 Tromsø, Norway. Electronic address: layiadekoya@gmail.com.
authors.forename: Olayiwola A
authors.initials: OA
authors.lastname: Adekoya
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: Department of Medical Biology, Faculty of Health Sciences, UiT - The Arctic University of Norway, NO-9037 Tromsø, Norway.
authors.forename: Yimingjiang
authors.initials: Y
authors.lastname: Wuxiuer
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: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: Sérgio M
authors.initials: SM
authors.lastname: Marques
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
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: Dipartimento di Biologia, Unità di Biochimica, Università di Pisa, Via San Zeno 51, 56127 Pisa, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cercignani
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
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006877:Hydroxamic Acids / Q000737:chemistry*; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011485:Protein Binding; D017385:Sequence Homology; D013379:Substrate Specificity; D013820:Thermolysin / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006877:Hydroxamic Acids; D008024:Ligands; D061965:Matrix Metalloproteinase Inhibitors; D013820:Thermolysin
keywords: Docking and scoring; Enzyme inhibitors; Matrix metalloproteinase; Pseudolysin; Thermolysin