by Peter Nollert
August 21, 2009 14:00
The main use of protein structures in pharma and biotech is of course guiding medicinal chemists in their effort to synthesize better compounds to bind to target proteins. To do this, it is necessary to get structures of protein-ligand complexes. In my discussions with industrial crystallographers I sense that these days more than half of all drug discovery projects are supported by X-ray crystallographic efforts. Hence drug discovery efforts can be effected in lead discovery, for instance via fragment-based screening or in the later phase of lead optimization. Both methodologies require the ligand to associate with the protein either before crystallization or after crystallization. The reality is though that the corresponding experiments, co-crystallization or ligand soaking don't always work. There are lots of reasons why they may not work. What's the back-up plan when soaking or co-crystallization experiments fail?
Cross-linking crystals and soaking them with ligands has worked for PDE10 (human phosphodiesterase 10a) - see this reference. Initially only apo PDE10 crystals could be grown. Ligands did not show up in the corresponding X-ray structures, neither after soaking apo crystals with ligands nor by crystallizing PDE10 together with the ligand. Once the PDE Crystals were cross-linked with glutardialdahyde though, and ligands were soaked in, X-ray structures with ligand bound were obtained.
Another trick in our toolbox,
Peter