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 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.
Ansaris, Four Valley Square, 512 East Township Line Road, Blue Bell, PA 19422, USA. kmistry@earthlink.net
Kristofer
K
Moffett
Zenon
Z
Konteatis
Duyan
D
Nguyen
Rupa
R
Shetty
Jennifer
J
Ludington
Ted
T
Fujimoto
Kyoung-Jin
KJ
Lee
Xiaomei
X
Chai
Haridasan
H
Namboodiri
Michael
M
Karpusas
Bruce
B
Dorsey
Frank
F
Guarnieri
Marina
M
Bukhtiyarova
Eric
E
Springman
Enrique
E
Michelotti
D000255:Adenosine Triphosphate / Q000737:chemistry; D000818:Animals; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D003907:Dexamethasone / Q000494:pharmacology; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry*; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
C553185:DFG peptide; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D013876:Thiophenes; D003907:Dexamethasone; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases