Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD)

Discovery of a new class of DFG-out p38 alpha kinase inhibitors with no hinge interaction is described. A computationally assisted, virtual fragment-based drug design (vFBDD) platform was utilized to identify novel non-aromatic fragments which make productive hydrogen bond interactions with Arg 70 on the alpha C-helix. Molecules incorporating these fragments were found to be potent inhibitors of p38 kinase. X-ray co-crystal structures confirmed the predicted binding modes. A lead compound was identified as a potent (p38 alpha IC(50) = 22 nM) and highly selective (>= 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor. (C) 2011 Elsevier Ltd. All rights reserved.