Virtual screen to NMR (VS2NMR): Discovery of fragment hits for the CBP bromodomain

摘要: Overexpression of the CREB-binding protein (CBP), a bromodomain-containing transcription coactivator involved in variety cellular processes, has been observed several types cancer with correlation to aggressiveness. We have screened library nearly 1500 fragments by high-throughput docking into CBP bromodomain followed binding energy evaluation using force field electrostatic solvation. Twenty 39 selected virtual screening are positive one or more ligand-observed nuclear magnetic resonance (NMR) experiments. Four crystal structures complex silico hits validate pose predicted docking. Thus, success ratio procedure is 50% 10% if considers validation NMR spectroscopy X-ray crystallography, respectively. Compounds 1 and 3 show favorable ligand efficiency two different vitro assays. The structure brominated pyrrole suggests fragment growing Suzuki coupling.