A combination of F-19 NMR and surface plasmon resonance for site-specific hit selection and validation of fragment molecules that bind to the ATP-binding site of a kinase

作者：Nagatoishi Satoru; Yamaguchi Sou; Katoh Etsuko^*; Kajita Keita; Yokotagawa Takane; Kanai Satoru; Furuya Toshio; Tsumoto Kouhei^*

来源：Bioorganic & Medicinal Chemistry, 2018, 26(8): 1929-1938.

DOI：10.1016/j.bmc.2018.02.041

• F-19 NMR
• Surface plasmon resonance (SPR)
• Drug screening
• Fragment-based drug discovery
• Kinase

F-19 NMR has recently emerged as an efficient, sensitive tool for analyzing protein binding to small molecules, and surface plasmon resonance (SPR) is also a popular tool for this purpose. Herein a combination of F-19 NMR and SPR was used to find novel binders to the ATP-binding pocket of MAP kinase extracellular regulated kinase 2 (ERK2) by fragment screening with an original fluorinated-fragment library. The F-19 NMR screening yielded a high primary hit rate of binders to the ERK2 ATP-binding pocket compared with the rate for the SPR screening. Hit compounds were evaluated and categorized according to their ability to bind to different binding sites in the ATP-binding pocket. The binding manner was characterized by using isothermal titration calorimetry and docking simulation. Combining F-19 NMR with other biophysical methods allows the identification of multiple types of hit compounds, thereby increasing opportunities for drug design using preferred fragments.

• 出版日期2018-5-1