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 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.
Singh
Juswinder
J
Biogen Inc, 12 Cambridge Center, Cambridge, MA 02142, USA. juswinder_singh@biogen.com
Chuaqui
Claudio E
CE
Boriack-Sjodin
P Ann
PA
Lee
Wen Cherng
WC
Pontz
Timothy
T
Corbley
Michael J
MJ
Cheung
H-Kam
HK
Arduini
Robert M
RM
Mead
Jonathan N
JN
Newman
Miki N
MN
Papadatos
James L
JL
Bowes
Scott
S
Josiah
Serene
S
Ling
Leona E
LE
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
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