title: Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry.
abstract: A critical issue in drug discovery utilizing combinatorial chemistry as part of the discovery process is the choice of scaffolds to be used for a proper presentation, in a three-dimensional space, of the critical elements of structure necessary for molecular recognition (binding) and information transfer (agonist/ antagonist). In the case of polypeptide ligands, considerations related to the properties of various backbone structures (alpha-helix, beta-sheets, etc.; phi, psi space) and those related to three-dimensional presentation of side-chain moieties (topography; chi (chi) space) must be addressed, although they often present quite different elements in the molecular recognition puzzle. We have addressed aspects of this problem by examining the three-dimensional 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 similar. We suggest a topographical approach involving design in chi space to deal with these problems.
authors.affiliation: Department of Chemistry, University of Arizona, Tucson 85721, USA.
authors.forename: V J
authors.initials: VJ
authors.lastname: Hruby
authors.forename: M
authors.initials: M
authors.lastname: Shenderovich
authors.forename: K S
authors.initials: KS
authors.lastname: Lam
authors.forename: M
authors.initials: M
authors.lastname: Lebl
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D003198:Computer Simulation; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D018716:Molecular Mimicry; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D019809:Streptavidin
chemical_list: D001426:Bacterial Proteins; D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D019809:Streptavidin