Hesterkamp T, Barker J, Davenport A, Whittaker M
Evotec, Schnackenburgallee 114, D-22525 Hamburg, Germany.
Curr Top Med Chem. 2007;7(16):1582-91. doi: 10.2174/156802607782341064.
Novel starting points for medicinal chemistry programmes can be effectively identified by screening libraries of fragment molecules in biochemical assays at high concentration. The key to success with this approach is the combination of a high quality fragment library with sensitive biochemical screening methods. There are an increasing number of literature reports where weakly active fragment molecules have been identified by high concentration biochemical assays. We have successfully demonstrated the use of high concentration screening of fragments, using a portfolio of single-molecule Fluorescence Correlation Spectroscopy (FCS+plus) detection techniques to ensure the highest reproducibility and sensitivity, and have determined the binding mode of active fragments to target proteins by X-ray crystallography. Further biophysical detection methods are reviewed for their applicability to studies of fragment binding.
通过在生化分析中高浓度筛选片段分子库，可以有效地确定药物化学项目的新起点。这种方法成功的关键在于高质量片段库与灵敏生化筛选方法的结合。越来越多的文献报道通过高浓度生化分析鉴定出了弱活性片段分子。我们已经成功地证明了使用单分子荧光相关光谱（FCS+plus）检测技术组合对片段进行高浓度筛选，以确保最高的重现性和灵敏度，并通过X射线晶体学确定了活性片段与靶蛋白的结合模式。本文还综述了其他生物物理检测方法在片段结合研究中的适用性。
