Section 22.4.5.10. Modelling applications that use CSD data

Predicting binding modes of ligands at protein binding sites is a problem of paramount importance in drug design. One approach to this problem is to attempt to dock the ligand directly into the binding site. There are several protein–ligand docking programs available, e.g. DOCK (see Kuntz et al., 1994), GRID (Goodford, 1985), FLExX and FLExS (Rarey et al., 1996; Lemmen & Lengauer, 1997), and GOLD (Jones et al., 1995, 1997). The docking program GOLD, developed by the University of Sheffield, Glaxo Wellcome and the CCDC, and which has the high docking success rate of 73%, uses a small torsion library, based on the data from the CSD, to explore the conformational space of the ligand. Its hydrogen-bond geometries and fitness functions are also partly based on CSD data. In the future, we intend to create a more direct link between the crystallographic data and the docking program, via IsoStar and the developing torsion library.

Another approach to the prediction of binding modes is to calculate the energy fields for different probes at each position of the binding site, for instance using the GRID program (Goodford, 1985). The resulting maps can be displayed as contoured surfaces which can assist in the prediction and understanding of binding modes of ligands. CCDC is developing a program called SuperStar (Verdonk et al., 1999) which uses a similar approach to that of the X-SITE program (Singh et al., 1991; Laskowski et al., 1996). However, SuperStar uses non-bonded interaction data from the CSD rather than the protein side chain–side chain interaction data employed in X-SITE. Thus, for a given binding site and contact group (probe), SuperStar selects the appropriate scatter plots from the IsoStar library, superimposes the scatter plots on the relevant functional groups in the binding site, and transforms them into one composite probability map. Such maps can then, for example, be used to predict where certain functional groups are likely to interact with the binding site. The strength of SuperStar is that it is based entirely on experimental data (although this is also the cause of some limitations). The fields simply represent what has been observed in crystal strucures. We are currently verifying SuperStar on a test set of more than 100 protein–ligand complexes from the PDB and preliminary results are encouraging.

Finally, CSD data are used in several de novo design programs. These types of programs, e.g. LUDI (Böhm, 1992a,b), predict novel ligands that will interact favourably with a given protein and use hydrogen-bond geometries from the CSD (indirectly) to position their structural fragments in the binding site.