Discovery of a novel class of non-ATP site DFG-out state p38 inhibitors utilizing computationally assisted virtual fragment-based drug design (vFBDD) |
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Authors: | 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 |
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Affiliation: | Ansaris, Four Valley Square, 512 East Township Line Road, Blue Bell, PA 19422, USA. kmistry@earthlink.net |
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Abstract: | 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 IC(50)=22 nM) and highly selective (≥ 150-fold against 150 kinase panel) DFG-out p38 kinase inhibitor. |
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Keywords: | TNF-α, tumor necrosis factor alpha IL, interleuken RA, rheumatoid arthritis MAPK, mitogen activated protein kinase ATP, adenosine triphosphate COPD, chronic obstructive pulmonary disease FBDD, fragment-based drug design LPS, lipopolysaccharide PBMC, peripheral blood mononuclear cells FFP, fresh-frozen plasma GCMC, grand canonical Monte Carlo |
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