Reporter Ligand NMR Screening Method for 2-Oxoglutarate Oxygenase Inhibitors

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• 作者：Ivanhoe K. H. Leung ; Marina Demetriades ; Adam P. Hardy ; Clarisse Lejeune ; Tristan J. Smart ; Andrea Sz枚ll枚ssi ; Akane Kawamura ; Christopher J. Schofield ; Timothy D. W. Claridge
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 24, 2013
• 年：2013
• 卷：56
• 期：2
• 页码：547-555
• 全文大小：385K
• 年卷期：v.56,no.2(January 24, 2013)
• ISSN：1520-4804

文摘

The human 2-oxoglutarate (2OG) dependent oxygenases belong to a family of structurally related enzymes that play important roles in many biological processes. We report that competition-based NMR methods, using 2OG as a reporter ligand, can be used for quantitative and site-specific screening of ligand binding to 2OG oxygenases. The method was demonstrated using hypoxia inducible factor hydroxylases and histone demethylases, and K_D values were determined for inhibitors that compete with 2OG at the metal center. This technique is also useful as a screening or validation tool for inhibitor discovery, as exemplified by work with protein-directed dynamic combinatorial chemistry.