DESIGN CONSIDERATIONS AND COMPUTER MODELING RELATED TO THE DEVELOPMENT OF MOLECULAR SCAFFOLDS AND PEPTIDE MIMETICS FOR COMBINATORIAL CHEMISTRY

A critical issue in drug discovery utilizing combinatorial chemistry a s part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critic al elements of structure necessary for molecular recognition (binding) and information transfer (agonist/antagonist). In the case of polypep tide ligands, considerations related to the properties of various back bone structures (alpha-helix, beta-sheets, etc.: phi psi space) and th ose related to three-dimensional presentation of side-chain moieties ( topography; chi (chi) space) must be addressed, although they often pr esent quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensi onal structures of chemically different scaffolds at various distances from the scaffold to evaluate their putative diversity. We find that chemically diverse scaffolds can readily become topographically simila r. We suggest a topographical approach involving design in chi space t o deal with these problems.