Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFbeta receptor kinase (TbetaRI)

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 interacti...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2003-12, Vol.13 (24), p.4355-4359
Main Authors: Singh, Juswinder, Chuaqui, Claudio E, Boriack-Sjodin, P Ann, Lee, Wen Cherng, Pontz, Timothy, Corbley, Michael J, Cheung, H-Kam, Arduini, Robert M, Mead, Jonathan N, Newman, Miki N, Papadatos, James L, Bowes, Scott, Josiah, Serene, Ling, Leona E
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:0960-894X