GlaxoSmithKline R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.
J Med Chem. 2011 Jul 28;54(14):5131-43. doi: 10.1021/jm200349b. Epub 2011 Jun 23.
A kinase-focused screening set of fragments has been assembled and has proved successful for the discovery of ligand-efficient hits against many targets. Here we present some of our general conclusions from this exercise. Notably, we present the first profiling results for literature fragments that have previously been used as starting points for optimization against individual kinases. We consider the importance of screening format and the extent to which selectivity is helpful in selecting fragments for progression. Results are also outlined for fragments targeting the DFG-out conformation and for atypical kinases such as PIM1 and lipid kinases.
激酶为靶点的小分子文库筛选已经建立，并在发现针对许多靶点的高效配体小分子方面取得了成功。在这里，我们将展示从这项工作中得出的一些普遍结论。值得注意的是，我们首次提供了文献报道的小分子片段的初步筛选结果，这些片段之前曾被用作针对个别激酶进行优化的起始点。我们考虑了筛选模式的重要性，以及在选择用于进展的片段时选择性的帮助程度。同时还概述了针对 DFG-out 构象的片段和非典型激酶（如 PIM1 和脂质激酶）的结果。
