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

Juswinder Singh, Claudio E Chuaqui, P Ann Boriack-Sjodin, Wen Cherng Lee, Timothy Pontz, Michael J Corbley, H-Kam Cheung, Robert M Arduini, Jonathan N Mead, Miki N Newman, James L Papadatos, Scott Bowes, Serene Josiah, Leona E Ling

Index: Bioorg. Med. Chem. Lett. 13 , 4355-4359, (2003)

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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.