Abstract
We describe the discovery, using shape-based virtual screening, of a potent, ATP site-directed inhibitor of the TbetaRI kinase, an important and novel drug target for fibrosis and cancer. The first detailed report of a TbetaRI kinase small molecule co-complex confirms the predicted binding interactions of our small molecule inhibitor, which stabilizes the inactive kinase conformation. Our results validate shape-based screening as a powerful tool to discover useful leads against a new drug target.
MeSH terms
-
Adenosine Triphosphate / metabolism
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / pharmacology
-
Binding Sites
-
Drug Evaluation, Preclinical / methods
-
Enzyme Inhibitors / chemical synthesis*
-
Enzyme Inhibitors / chemistry
-
Enzyme Inhibitors / pharmacology
-
Kinetics
-
Molecular Conformation
-
Phosphorylation
-
Protein Conformation
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Receptor, Transforming Growth Factor-beta Type I
-
Receptors, Transforming Growth Factor beta
-
User-Computer Interface
Substances
-
Antineoplastic Agents
-
Enzyme Inhibitors
-
Receptors, Transforming Growth Factor beta
-
Adenosine Triphosphate
-
Protein Serine-Threonine Kinases
-
Receptor, Transforming Growth Factor-beta Type I