890926-79-1Relevant academic research and scientific papers
Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD)
Moffett, Kristofer,Konteatis, Zenon,Nguyen, Duyan,Shetty, Rupa,Ludington, Jennifer,Fujimoto, Ted,Lee, Kyoung-Jin,Chai, Xiaomei,Namboodiri, Haridasan,Karpusas, Michael,Dorsey, Bruce,Guarnieri, Frank,Bukhtiyarova, Marina,Springman, Eric,Michelotti, Enrique
supporting information; experimental part, p. 7155 - 7165 (2012/01/15)
Discovery of a new class of DFG-out p38α 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 αC-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 (p38α IC50 = 22 nM) and highly selective (≥150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.
