Hesterkamp Thomas, Whittaker Mark
Evotec AG, Schnackenburgallee 114, Hamburg, Germany.
Curr Opin Chem Biol. 2008 Jun;12(3):260-8. doi: 10.1016/j.cbpa.2008.02.005. Epub 2008 Mar 19.
Fragment-based drug discovery has the potential to supersede traditional high throughput screening based drug discovery for molecular targets amenable to structure determination. This is because the chemical diversity coverage is better accomplished by a fragment collection of reasonable size than by larger HTS collections. Furthermore, fragments have the potential to be efficient target binders with higher probability than more elaborated drug-like compounds. The selection of the fragment screening technique is driven by sensitivity and throughput considerations, and we advocate in the present article the use of high concentration bioassays in conjunction with NMR-based hit confirmation. Subsequent ligand X-ray structure determination of the fragment ligand in complex with the target protein by co-crystallisation or crystal soaking can focus on confirmed binders.
对于适合进行结构测定的分子靶点，基于片段的药物发现有潜力取代传统的基于高通量筛选的药物发现。这是因为合理规模的片段库比更大的高通量筛选库能更好地实现化学多样性覆盖。此外，片段比更复杂的类药物化合物更有可能成为高效的靶点结合物。片段筛选技术的选择受灵敏度和通量因素驱动，在本文中我们提倡使用高浓度生物测定法并结合基于核磁共振的命中确认。随后通过共结晶或晶体浸泡对与靶蛋白复合的片段配体进行配体X射线结构测定可聚焦于已确认的结合物。
