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ISI Journal Citation Reports © Ranking: 2014: 19/59 (Chemistry Medicinal); 83/255 (Pharmacology & Pharmacy)
Online ISSN: 1860-7187
November 08, 2010
VIP: Characterization of C-Alkyl Amidines as Bioavailable Covalent Reversible Inhibitors of Human DDAH-1
Matthew Lluis, Yun Wang, Arthur F. Monzingo, Walter Fast,* Jon D. Robertus
Abnormally high levels of nitric oxide (NO) have been associated in certain cases with tumor growth. In their efforts to address this, a team led by Walter Fast at the University of Texas at Austin set out to develop a single drug that blocks NO production by inhibiting two different enzyme targets. One target is NO synthase, the direct source of NO, and the other is DDAH-1, which degrades an endogenous inhibitor of NO synthase.
Fast and colleagues used a click chemistry mediated activity probe to gauge a series of dual-targeted inhibitors for potency within cultured cells. The most potent of the series was characterized in detail by X-ray crystallography and calorimetry to elucidate its interactions with the DDAH-1 active site. Their study is a combination of cell-based and in vitro work that dissects the contribution of an unusual covalent reversible bond to a compound's potency, and provides valuable information for the development of new NO-blocking drugs.
Received September 13, 2010; published online October 26, 2010, DOI: 10.1002/cmdc.201000392.