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

• Published in: Bioorganic & medicinal chemistry letters Vol. 13; no. 24; pp. 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: Journal Article
• Language: English
• Published: England 15-12-2003
• 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
• ISSN: 0960-894X

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.