3tgm

Publication Abstract from PubMed

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 approximately 15 times more potent (IC(50) = 0.27+/-0.07 microM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC(50) = 4.0+/-1.8 microM). 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.

A novel, "double-clamp" binding mode for human heme oxygenase-1 inhibition.,Rahman MN, Vlahakis JZ, Vukomanovic D, Lee W, Szarek WA, Nakatsu K, Jia Z PLoS One. 2012;7(1):e29514. Epub 2012 Jan 19. PMID:22276118^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.