Site-directed structure generation by fragment-joining

Recently, several computer programs for de novo ligand design have been described that construct novel molecules by combining several fragments into one molecule. The present review discusses the advantages and disadvantages of this fragment-based approach to de novo design. The computer program LUDI for automated structure-based ligand design is described in some detail. This program constructs possible new ligands for a given protein of known three-dimensional structure. In addition, LUDI can also be used for 3D database searching. LUDI is based upon rules about energetically favorable nonbonded contact geometries between functional groups of the protein and the ligand which are derived from a statistical analysis of crystal packings of organic molecules. All putative ligands retrieved or constructed by LUDI are scored by a simple scoring function that was fitted to experimentally determined binding constants of protein-ligand complexes. LUDI is a fast program that is suitable for interactive usage.