Multiple and Single Binding Modes of Fragment-Like Kinase Inhibitors Revealed by Molecular Modeling, Residue Type-Selective Protonation, and Nuclear Overhauser Effects

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• 作者：Keith L. Constantine ; Luciano Mueller ; William J. Metzler ; Patricia A. McDonnell ; Gordon Todderud ; Valentina Goldfarb ; Yi Fan ; John A. Newitt ; Susan E. Kiefer ; Mian Gao ; David Tortolani ; Wayne Vaccaro
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：October 9, 2008
• 年：2008
• 卷：51
• 期：19
• 页码：6225-6229
• 全文大小：209K
• 年卷期：v.51,no.19(October 9, 2008)
• ISSN：1520-4804

文摘

Fragment-like inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK2) include 5-hydroxyisoquinoline (IC₅₀ ∼ 85 μM). Modeling studies identified four possible binding modes for this compound. Two-dimensional ¹H−¹H NOESY data obtained with selectively protonated samples of MK2 in complex with 5-hydroxyisoquinoline demonstrated that two of the four predicted binding modes are well populated. A second small isoquinoline was subsequently shown to bind in a single mode. NMR and modeling studies using this general approach are expected to facilitate “scaffold hopping” and structure-guided elaborations of fragment-like kinase inhibitor cores.