title: Structural insights into human heme oxygenase-1 inhibition by potent and selective azole-based compounds.
abstract: The development of heme oxygenase (HO) inhibitors, especially those that are isozyme-selective, promises powerful pharmacological tools to elucidate the regulatory characteristics of the HO system. It is already known that HO has cytoprotective properties and may play a role in several disease states, making it an enticing therapeutic target. Traditionally, the metalloporphyrins have been used as competitive HO inhibitors owing to their structural similarity with the substrate, heme. However, given heme's important role in several other proteins (e.g. cytochromes P450, nitric oxide synthase), non-selectivity is an unfortunate side-effect. Reports that azalanstat and other non-porphyrin molecules inhibited HO led to a multi-faceted effort to develop novel compounds as potent, selective inhibitors of HO. This resulted in the creation of non-competitive inhibitors with selectivity for HO, including a subset with isozyme selectivity for HO-1. Using X-ray crystallography, the structures of several complexes of HO-1 with novel inhibitors have been elucidated, which provided insightful information regarding the salient features required for inhibitor binding. This included the structural basis for non-competitive inhibition, flexibility and adaptability of the inhibitor binding pocket, and multiple, potential interaction subsites, all of which can be exploited in future drug-design strategies.
authors.affiliation: 1Department of Biomedical and Molecular Sciences, and 2Department of Chemistry, Queen’s University, Kingston, Ontario, Canada.
authors.forename: Mona N
authors.initials: MN
authors.lastname: Rahman
authors.forename: Dragic
authors.initials: D
authors.lastname: Vukomanovic
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Vlahakis
authors.forename: Walter A
authors.initials: WA
authors.lastname: Szarek
authors.forename: Kanji
authors.initials: K
authors.lastname: Nakatsu
authors.forename: Zongchao
authors.initials: Z
authors.lastname: Jia
mesh_terms: D001393:Azoles / Q000737:chemistry*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry*; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000145:classification*; D006801:Humans; D013329:Structure-Activity Relationship
chemical_list: D001393:Azoles; D004791:Enzyme Inhibitors; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1