PRO-LIGAND - AN APPROACH TO DE-NOVO MOLECULAR DESIGN .4. APPLICATION TO THE DESIGN OF PEPTIDES

In some instances, peptides can play an important role in the discover y of lead compounds. This paper describes the peptide design facility of the de novo drug design package, PRO_LIGAND. The package provides a unified framework for the design of peptides that are similar or comp lementary to a specified target. The approach uses single amino acid r esidues, selected from preconstructed libraries of different residues and conformations, and places them on top of predefined target interac tion sites. This approach is a well-tested methodology for the design of organics but has not been used for peptides before. Peptides repres ent a difficulty because of their great conformational flexibility and a study of the advantages and disadvantages of this simple approach i s an important step in the development of design tools. After a descri ption of our general approach, a more detailed discussion of its adapt ation to peptides is given. The method is then applied to the design o f peptide-based inhibitors to HIV-1 protease and the design of structu ral mimics of the surface region of lysozyme. The results are encourag ing and point the way towards further development of interaction site- based approaches for peptide design.