Fig. 14.

Design strategy for inhibitors of p38 MAPK. (A) Key interactions of BIRB-796 inhibitor with MAPK. (B) A fragment linking strategy to link two seed structures was applied using LigBuilder. A tert-butyl phenyl fragment was used in the first pocket, whereas a carbonyl fragment was used to access the hydrogen bond with Met109 in the second site. An N-formyl group was attached to the first seed fragment to access hydrogen bonds with Glu71 and Asp168. (C) General structure of optimized structures which showed potent activity. (D) R group for compound 28, which showed IC₅₀ value of 83 nM. Adapted from Cogan et al. (2008).