Biological diversity from a structurally diverse library: systematically scanning conformational space using a pyranose scaffold

J Med Chem. 2010 Aug 12;53(15):5576-86. doi: 10.1021/jm1002777.

Abstract

Success in discovering bioactive peptide mimetics is often limited by the difficulties in correctly transposing known binding elements of the active peptide onto a small and metabolically more stable scaffold while maintaining bioactivity. Here we describe a scanning approach using a library of pyranose-based peptidomimetics that is structurally diverse in a systematic manner, designed to cover all possible conformations of tripeptide motifs containing two aromatic groups and one positive charge. Structural diversity was achieved by efficient selection of various chemoforms, characterized by a choice of pyranose scaffold of defined chirality and substitution pattern. A systematic scanning library of 490 compounds was thus designed, produced, and screened in vitro for activity at the somatostatin (sst(1-5)) and melanin-concentrating hormone (MCH(1)) receptors. Bioactive compounds were found for each target, with specific chemoform preferences identified in each case, which can be used to guide follow-on drug discovery projects without the need for scaffold hopping.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Animals
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Databases, Factual
  • Humans
  • Models, Molecular
  • Molecular Conformation
  • Molecular Mimicry
  • Monosaccharides / chemistry*
  • Monosaccharides / pharmacology
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Radioligand Assay
  • Receptors, Somatostatin / antagonists & inhibitors
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • MCHR1 protein, human
  • Monosaccharides
  • Oligopeptides
  • Receptors, Somatostatin