title: Successful shape-based virtual screening: the discovery of a potent inhibitor of the type I TGFbeta receptor kinase (TbetaRI).
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.
authors.affiliation: Biogen Inc, 12 Cambridge Center, Cambridge, MA 02142, USA. juswinder_singh@biogen.com
authors.forename: Juswinder
authors.initials: J
authors.lastname: Singh
authors.forename: Claudio E
authors.initials: CE
authors.lastname: Chuaqui
authors.forename: P Ann
authors.initials: PA
authors.lastname: Boriack-Sjodin
authors.forename: Wen Cherng
authors.initials: WC
authors.lastname: Lee
authors.forename: Timothy
authors.initials: T
authors.lastname: Pontz
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Corbley
authors.forename: H-Kam
authors.initials: HK
authors.lastname: Cheung
authors.forename: Robert M
authors.initials: RM
authors.lastname: Arduini
authors.forename: Jonathan N
authors.initials: JN
authors.lastname: Mead
authors.forename: Miki N
authors.initials: MN
authors.lastname: Newman
authors.forename: James L
authors.initials: JL
authors.lastname: Papadatos
authors.forename: Scott
authors.initials: S
authors.lastname: Bowes
authors.forename: Serene
authors.initials: S
authors.lastname: Josiah
authors.forename: Leona E
authors.initials: LE
authors.lastname: Ling
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008968:Molecular Conformation; D010766:Phosphorylation; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta; D014584:User-Computer Interface
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I