Discovery of potent p38 alpha MAPK inhibitors through a funnel like workflow combining in silico screening and in vitro validation

摘要

This work describes the rational discovery of novel chemotypes of p38 alpha MAPK inhibitors using a funnel approach consisting of several computer-aided drug discovery methods and biological experiments. Among the identified hits, four compounds belonging to different chemical families showed IC50 values lower than 10 mu M. In particular, the 1,4-benzodioxane derivative 5 turned out to be a potent and efficient p38 alpha MAPK inhibitor having IC50 = 0.07 mu M, and LEexp and LipE values of 0.38 and 4.8, respectively; noteworthy, the compound had also a promising kinase selectivity profile and the capability to suppress p38 alpha MAPK effects in human immune cells.