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

Article Details

Citation

Copy to clipboard

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

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

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7155-65. doi: 10.1016/j.bmcl.2011.09.078. Epub 2011 Sep 28.

PubMed ID

22014550 [ View in PubMed

]

Abstract

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)=22 nM) and highly selective (>/= 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Doramapimod	Mitogen-activated protein kinase 14	IC 50 (nM)	20	N/A	N/A	Details