Sandeep Pal; Zandile Nare; Vincenzo A. Rao; Brian O. Smith; Ian Morrison; Edward A. Fitzgerald; Andrew Scott; Matilda Jane Bingham; Thomas Pesnot
ChemMedChem, 2024, e202300590
https://doi.org/10.1002/cmdc.202300590

Abstract

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 parameters. In addition to the excellent in silico/in vitro confirmation rate demonstrated with BRPF1b, binding kinetics are determined, and binding topologies predicted for all hits. BioPALS is a lean, data-rich, and standardized approach to hit identification applicable to wide range of biological targets.