A Back-to-Front Fragment-Based Drug Design Search Strategy Targeting the DFG-Out Pocket of Protein Tyrosine Kinases
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- 作者：Hidehisa Iwata ; Hideyuki Oki ; Kengo Okada ; Terufumi Takagi ; Michiko Tawada ; Yasushi Miyazaki ; Shinichi Imamura ; Akira Hori ; J. David Lawson ; Mark S. Hixon ; Hiroyuki Kimura ; Hiroshi Miki
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：April 12, 2012
- 年：2012
- 卷：3
- 期：4
- 页码：342-346
- 全文大小：350K
- 年卷期：v.3,no.4(April 12, 2012)
- ISSN：1948-5875
文摘
We present a straightforward process for the discovery of novel back pocket-binding fragment molecules against protein tyrosine kinases. The approach begins by screening against the nonphosphorylated target kinase with subsequent counterscreening of hits against the phosphorylated enzyme. Back pocket-binding fragments are inactive against the phosphorylated kinase. Fragment molecules are of insufficient size to span both regions of the ATP binding pocket; thus, the outcome is binary (back pocket-binding or hinge-binding). Next, fragments with the appropriate binding profile are assayed in combination with a known hinge-binding fragment and subsequently with a known back pocket-binding fragment. Confirmation of back pocket-binding by Yonetani鈥揟heorell plot analysis progresses candidate fragments to crystallization trials. The method is exemplified by a fragment screening campaign against vascular endothelial growth factor receptor 2, and a novel back pocket-binding fragment is presented.