Accelerating BRPF1b hit identification with BioPhysical and Active Learning Screening (BioPALS).

We report the development of BioPhysical and Active Learning Screening (BioPALS); a rapid and versatile hit identification protocol combining AI-powered virtual screening with a GCI-driven biophysical confirmation workflow. Its application to the BRPF1b bromodomain afforded a range of novel micromolar binders with favorable ADMET properties. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics were determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to a wide range of biological targets.

Eating, sleeping and rewarding: orexin receptors and their antagonists.

The orexin system plays a key role in the control of eating, sleeping and rewarding. This review summarizes the latest developments in the identification of orexin receptor antagonists. By using a selective orexin-1 receptor antagonist, SB-334867-A (GlaxoSnzithKline plc), the in vivo futctions of both the orexin-1 and orexin-2 receptors have been elucidated. This review also sunmmarizes the literature and current opinions up to May 2006 on the therapeutic utility of orexin receptor antagonists for the treatment of eating disorders, sleeping disorders and drug addiction.