High-throughput X-ray crystallography for drug discovery

Knowledge of the three-dimensional structures of protein targets has the potential to greatly accelerate drug discovery, but technical challenges and time constraints have traditionally limited its use to lead optimization. Its application is now being extended beyond structure determination into new approaches for lead discovery. Structure-activity relationships by nuclear magnetic resonance have been widely used to detect ligand binding and to give some indication of the location of the binding site. X-ray crystallography has the advantage of defining ligand-binding sites with greater certainty. High-throughput approaches make this method applicable to screening to identify molecular fragments that bind protein targets, and to defining precisely their binding sites. X-ray crystallography can then be used as a rapid technique to guide the elaboration of the fragments into larger molecular weight compounds that might be useful leads for drug discovery.