A fragment-based approach for the discovery of isoform-specific p38alpha inhibitors.
In this study, we describe a novel approach for lead discovery against protein kinases, pharmacophore by interligand nuclear Overhauser effect (ILOE), in which a pair of ligands that bind to adjacent pockets on the target surface is identified by the detection of protein-mediated ILOEs. We demonstrate that a pharmacophore-based search guided by experimental binding data of weakly interacting fragments can be rapidly and efficiently used to identify (or synthesize) high-affinity, selective ligands. Targeting the inactive state of protein kinases represents a promising approach to achieve selectivity and cellular efficacy. In this respect, when we apply the method for the discovery of potent p38alpha inhibitors, we also demonstrate that the resulting bidentate compounds are highly selective and exhibit a cellular activity that parallels their in vitro binding to the inactive form of the kinase. The method is relatively simple and of general applicability, and as such we anticipate its potential implementation against a variety of macromolecular targets, including not only protein kinases but also those involved in protein-protein interactions or even nucleic acids.
Chen
Jinhua
J
Burnham Institute for Medical Research, 10901 North Pines Road, La Jolla, California 92037, USA.
Zhang
Ziming
Z
Stebbins
John L
JL
Zhang
Xiyun
X
Hoffman
Randy
R
Moore
Ambika
A
Pellecchia
Maurizio
M
D002460:Cell Line; D015195:Drug Design; D006801:Humans; D007527:Isoenzymes; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000096:biosynthesis
D007527:Isoenzymes; D008024:Ligands; D008070:Lipopolysaccharides; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D048308:Mitogen-Activated Protein Kinase 14