Search

Fragment-based drug discovery (FBDD), which involves small compounds <300 Da, has been recognized as one of the most powerful tools for drug discovery. In FBDD, the affinity of hit compounds tends to be low, and the analysis of protein-compound interactions becomes difficult. In an effort to overcome such difficulty, we developed a 19 F-NMR screening method optimizing a 19 F chemical library focusing on highly soluble monomeric molecules. Our method was successfully applied to four proteins, including protein kinases and a membrane protein. For FKBP12, hit compounds were carefully validated by protein thermal shift analysis, 1 H- 15 N HSQC NMR spectroscopy, and isothermal titration calorimetry to determine dissociation constants and model complex structures. It should be noted that the 1 H and 19 F saturation transfer difference experiments were crucial to obtaining highly precise model structures. The combination of 19 F-NMR analysis and the optimized 19 F chemical library enables the modeling of the complex structure made up of a weak binder and its target protein., Competing Interests: There are no conflicts of interest to declare., (This journal is © The Royal Society of Chemistry.)

We have observed the 1-bond (199)Hg-(15)N J-coupling ((1)J((199)Hg,(15)N) = 1050 Hz) within the Hg(II)-mediated thymine-thymine base pair (T-Hg(II)-T). This strikingly large (1)J((199)Hg,(15)N) is the first one for canonical sp(2)-nitrogen atoms, which can be a sensitive structure-probe of N-mercurated compounds and a direct evidence for N-mercuration.