title: A novel, "double-clamp" binding mode for human heme oxygenase-1 inhibition.
abstract: The development of heme oxygenase (HO) inhibitors is critical in dissecting and understanding the HO system and for potential therapeutic applications. We have established a program to design and optimize HO inhibitors using structure-activity relationships in conjunction with X-ray crystallographic analyses. One of our previous complex crystal structures revealed a putative secondary hydrophobic binding pocket which could be exploited for a new design strategy by introducing a functional group that would fit into this potential site. To test this hypothesis and gain further insights into the structural basis of inhibitor binding, we have synthesized and characterized 1-(1H-imidazol-1-yl)-4,4-diphenyl-2-butanone (QC-308). Using a carbon monoxide (CO) formation assay on rat spleen microsomes, the compound was found to be ∼15 times more potent (IC(50) = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC(50) = 4.0±1.8 µM). The crystal structure of hHO-1 with QC-308 revealed that the second phenyl group in the western region of the compound is indeed accommodated by a definitive secondary proximal hydrophobic pocket. Thus, the two phenyl moieties are each stabilized by distinct hydrophobic pockets. This "double-clamp" binding offers additional inhibitor stabilization and provides a new route for improvement of human heme oxygenase inhibitors.
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Canada.
authors.forename: Mona N
authors.initials: MN
authors.lastname: Rahman
authors.forename: Jason Z
authors.initials: JZ
authors.lastname: Vlahakis
authors.forename: Dragic
authors.initials: D
authors.lastname: Vukomanovic
authors.forename: Wallace
authors.initials: W
authors.lastname: Lee
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: D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D004791:Enzyme Inhibitors; D051547:Heme Oxygenase-1