A comparative study of fragment screening methods on the p38α kinase: new methods, new insights

• DOI: 10.1007/s10822-011-9454-9
• Publication Date: 2011-07-05T12:18:13Z
• Authors: Scott J. Pollack; Kim S. Beyer; Christopher Lock; Ilka Müller; David Sheppard; Mike Lipkin; David Hardick; Peter Blurton; Philip M. Leonard; Paul A. Hubbard; Daniel Todd; Christine M. Rich...; Thomas Ahrens; Manuel Baader; Doris O. Hafenbradl; Kate Hilyard; Roland W. Bürli
• Keywords: Microscale Thermophoresis; Fragment (logic)

The stress-activated kinase p38α was used to evaluate a fragment-based drug discovery approach using the BioFocus fragment library. Compounds were screened by surface plasmon resonance (SPR) on Biacore(™) T100 against and two selectivity targets. A sub-set of our library focus detailed follow-up analyses that included hit confirmation, affinity determination 24 confirmed, selective hits competition assays these with respect known ATP binding site inhibitor. In addition, functional activity assessed in biochemical assay mobility shift platform (LC3000, Caliper LifeSciences). selection fragments also evaluated fluorescence lifetime (FLEXYTE(™)) microscale thermophoresis (Nanotemper) technologies. good correlation between data for different found. Crystal structures solved four small molecules complexed p38α. Interestingly, as determined both X-ray analysis SPR experiments, three complexes involved at site, while fourth compound bound distal may offer potential novel target site. first round optimization around remotely has led identification series triazole-containing compounds. This could form basis developing active inhibitors. More broadly, it illustrates power combining range biophysical techniques facilitate development modulators other