title: How does binding of imidazole-based inhibitors to heme oxygenase-1 influence their conformation? Insights combining crystal structures and molecular modelling.
abstract: Heme oxygenase-1 (HO-1) inhibition is associated with antitumor activity. Imidazole-based analogues show effective and selective inhibitory potency of HO-1. In this work, five single-crystal structures of four imidazole-based compounds are presented, with an in-depth structural analysis. In order to study the influence of the conformation of the ligands on binding to protein, conformational data from crystallography are compared with quantum mechanics analysis and molecular docking studies. Molecular docking of imidazole-based analogues in the active site of HO-1 is in good agreement with the experimental structures. Inhibitors interact with the heme cofactor and a hydrophobic pocket (Met34, Phe37, Val50, Leu147 and Phe214) in the HO-1 binding site. An alternate binding mode can be hypothesized for some inhibitors in the series.
authors.affiliation: Chemistry Department (member of NAMEDIC), University of Namur, 61 Rue de Bruxelles, Namur B-5000, Belgium.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carletta
authors.affiliation: Chemistry Department (member of NAMEDIC), University of Namur, 61 Rue de Bruxelles, Namur B-5000, Belgium.
authors.forename: Anaëlle
authors.initials: A
authors.lastname: Tilborg
authors.affiliation: Chemistry Department (member of NAMEDIC), University of Namur, 61 Rue de Bruxelles, Namur B-5000, Belgium.
authors.forename: Laurence
authors.initials: L
authors.lastname: Moineaux
authors.affiliation: Chemistry Department (member of NAMEDIC), University of Namur, 61 Rue de Bruxelles, Namur B-5000, Belgium.
authors.forename: Jérôme
authors.initials: J
authors.lastname: de Ruyck
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, Catania I-95125, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Basile
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, Catania I-95125, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Salerno
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, Catania I-95125, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Romeo
authors.affiliation: Chemistry Department (member of NAMEDIC), University of Namur, 61 Rue de Bruxelles, Namur B-5000, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Wouters
authors.affiliation: Dipartimento di Scienze del Farmaco, Università degli Studi di Catania, Viale A. Doria 6 Ed. 2, Città Universitaria, Catania I-95125, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Guccione
mesh_terms: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects; D011789:Quantum Theory
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; C029899:imidazole; D051547:Heme Oxygenase-1
keywords: ab initio optimization; anticancer drugs; imidazole-based heme oxygenase inhibitors; molecular docking