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 (IC50 = 0.27±0.07 µM) than its monophenyl analogue, which is already a potent compound in its own right (QC-65; IC50 = 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.
Highlights
The heme oxygenase (HO) system comprises two active isozymes (HO-1 and HO-2) which are involved in the regioselective, oxidative cleavage of heme at the a-meso carbon
It was suggested that this secondary pocket was induced upon binding of inhibitor as it was not apparent in the high resolution native structure
It was postulated that it may accommodate the bulky group in the thio-(4-aminophenyl) region of azalanstat which we later refuted by the observation of the inducible binding mode of hHO-1 with QC-80 [31]
Summary
The heme oxygenase (HO) system comprises two active isozymes (HO-1 and HO-2) which are involved in the regioselective, oxidative cleavage of heme at the a-meso carbon. CO has been found to be one of the most important gasotransmitters in the body, with evidence demonstrating regulatory involvement in antiinflammatory, antiapoptotic, antiproliferative and vasodilatory effects [5,6,7,8]. Both biliverdin and bilirubin act to scavenge free radicals such as superoxide, peroxyl radicals and peroxynitrite, making them both powerful antioxidants [9,10,11]; bilirubin has been shown to provide protection against oxidative stressinduced pathologies [5]. HO-1 has been found to do be upregulated in several cancers, including pancreatic and prostate, and in response to several anticancer treatments [13,14,15]
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