A novel computational tool for automated structure-based drug design.

The computer program LUDI for automated structure-based drug design is described. The program constructs possible new ligands for a given protein of known three-dimensional structure. This novel approach is based upon rules about energetically favourable non-bonded contact geometries between functional groups of the protein and the ligand which are derived from a statistical analysis of crystal packings of organic molecules. In a first step small fragments are docked into the protein binding site in such a way that hydrogen bonds and ionic interactions can be formed with the protein and hydrophobic pockets are filled with lipophilic groups of the ligand. The program can then append further fragments onto a previously positioned fragment or onto an already existing ligand (e.g., a lead structure that one seeks to improve). It is also possible to link several fragments together by bridge fragments to form a complete molecule. All putative ligands retrieved or constructed by LUDI are scored. We use a simple scoring function that was fitted to experimentally determined binding constants of protein-ligand complexes. LUDI is a very fast program with typical execution times of 1-5 min on a work station and is therefore suitable for interactive usage.