Molecular modeling study of the induced-fit effect on kinase inhibition: the case of fibroblast growth factor receptor 3 (FGFR3)

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• 作者：Yan Li ; Michel Delamar ; Patricia Busca…
• 关键词：Targeted molecular dynamics ; FGFR3 ; Tyrosine kinase ; DFGout ; Inactivation process ; Conformational change ; Molecular docking ; Induced ; fit effect
• 刊名：Journal of Computer-Aided Molecular Design
• 出版年：2015
• 出版时间：July 2015
• 年：2015
• 卷：29
• 期：7
• 页码：619-641
• 全文大小：3,120 KB
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• 作者单位：Yan Li (1) (2)
  Michel Delamar (2)
  Patricia Busca (3)
  Guillaume Prestat (3)
  Laurent Le Corre (3)
  Laurence Legeai-Mallet (4)
  RongJing Hu (5)
  Ruisheng Zhang (5)
  Florent Barbault (2)
  
  1. Department of Chemistry, Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China
  2. ITODYS, UMR CNRS 7086, Univ Paris Diderot, Sorbonne Paris Cité, 15 rue J-A. de Ba?f, 75013, Paris, France
  3. UMR 8601 CNRS, Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, Université Paris Descartes, 45 rue des Saints-Pères, 75006, Paris, France
  4. INSERM U781, Institut Imagine, H?pital Necker-Enfants Malades, Université Paris Descartes, Sorbonne Paris Cité, 156 rue Vaugirard, Paris, France
  5. School of Information Science and Engineering, Lanzhou University, Lanzhou, 730000, Gansu, People’s Republic of China
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Physical Chemistry
  Computer Applications in Chemistry
  Animal Anatomy, Morphology and Histology
  
• 出版者：Springer Netherlands
• ISSN：1573-4951

文摘

Tyrosine kinases are a wide family of targets with strong pharmacological relevance. These proteins undergo large-scale conformational motions able to inactivate them. By the end of one of these structural processes, a new cavity is opened allowing the access to a specific type of inhibitors, called type II. The kinase domain of fibroblast growth factor receptor 3 (FGFR3) falls into this family of kinases. We describe here, for the first time, its inactivation process through target molecular dynamics. The transient cavity, at the crossroad between the DFGout and Cα helix out inactivation is herein explored. Molecular docking calculations of known ligands demonstrated that type II inhibitors are able to interact with this metastable transient conformation of FGFR3 kinase. Besides, supplemental computations were conducted and clearly show that type II inhibitors drive the kinase inactivation process through specific stabilization with the DFG triad. This induced-fit effect of type II ligands toward FGFR3 might be extrapolated to other kinase systems and provides meaningful structural information for future drug developments.