Abstract

Fragment-Based In Silico Discovery Of Potent And Selective Bromodomain Inhibitors

Amedeo Caflisch, Full Professor, University of Zurich

The fragment-based high-throughput docking campaigns carried out in our research group in the past three years have resulted in the identification of small molecules with ligand efficiency better than 0.30 kcal/mol per heavy atom for six human bromodomains: BRD4(1), CREBBP, BRPF1, ATAD2, BRD1, and BAZ2B. In the case of the CREBBP bromodomain, optimization of the initial hits by chemical synthesis of derivatives has resulted in several low-nanomolar binders with favorable ligand efficiency and selectivity of more than 1000 against BRD4(1). Thus, the screening of fragment libraries by docking is very efficient (24,000 molecules in a day on a commodity desktop) and results in high hit rates (25% to 50%).