Crystallographic screening using ultra-low-molecular-weight ligands to guide drug design
Marc O’Reilly, Anne Cleasby, Thomas G. Davies, Richard J. Hall, R. Frederick Ludlow, Christopher W. Murray, Dominic Tisi, Harren Jhoti · Drug Discovery Today · 2019
We present a novel crystallographic screening methodology (MiniFrags) that employs high-concentration aqueous soaks with a chemically diverse and ultra-low-molecular-weight library (heavy atom count 5–7) to identify ligand-binding hot and warm spots on proteins. We propose that MiniFrag screening represents a highly effective method for guiding optimisation of fragment-derived lead compounds or chemical tools and that the high screening hit rates reflect enhanced sampling of chemical space.