Publication Abstract from PubMed
Discovery of a new class of DFG-out p38alpha 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 alphaC-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 (p38alpha IC(50)=22nM) and highly selective (>/=150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.
Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD).,Moffett K, Konteatis Z, Nguyen D, Shetty R, Ludington J, Fujimoto T, Lee KJ, Chai X, Namboodiri H, Karpusas M, Dorsey B, Guarnieri F, Bukhtiyarova M, Springman E, Michelotti E Bioorg Med Chem Lett. 2011 Sep 28. PMID:22014550
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.