Design considerations and computer modeling related to the development of molecular scaffolds and peptide mimetics for combinatorial chemistry

Victor J. Hruby, Mark Shenderovich, Kit Lam, Michal Lebl

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 (α-helix, β-sheets, etc.; φ, ψ space) and those related to three-dimensional presentation of side-chain moieties (topography; χ (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.

Original languageEnglish (US)
Pages (from-to)46-56
Number of pages11
JournalMolecular Diversity
Volume2
Issue number1-2
StatePublished - 1996
Externally publishedYes

Keywords

  • Backbone conformation
  • Chi space
  • Scaffold design
  • Topographical design
  • Topography

ASJC Scopus subject areas

  • Chemistry (miscellaneous)
  • Drug Discovery
  • Organic Chemistry

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