Engineering metal complexes of chiral pentaazacrowns as privileged reverse-turn scaffolds

Ye Che, Bernard R. Brooks, Dennis P. Riley, Andrea J.H. Reaka, Garland R. Marshall

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Reverse turns are common structural motifs and recognition sites in protein/protein interactions. The design of peptidomimetics is often based on replacing the amide backbone of peptides by a non-peptidic scaffold while retaining the biologic mode of action. This study evaluates the potential of metal complexes of chiral pentaazacrowns conceptually derived by reduction of cyclic pentapeptides as reverse-turn mimetics. The possible conformations of metal complexes of chiral pentaazacrown scaffolds have been probed by analysis of 28 crystal structures complexed with six different metals (Mn, Fe, Co, Ni, Cu, and Zn). The solvated structures as well as the impact of complexation with different metals/oxidation states have been examined with density functional theory (DFT) calculation as explicitly represented by interactions with a single water molecule. The results suggest that most reverse-turn motifs seen in proteins could be mimicked effectively with a subset of metal complexes of chiral pentaazacrown scaffolds with an RMSD of approximately 0.3 Å. Due to the relatively fixed orientation of the pendant chiral side groups in these metal complexes, one can potentially elicit information about the receptor-bound conformation of the parent peptide from their binding affinities. The presence of 20 H-atoms on the pentaazacrown ring that could be functionalized as well as the conformational perturbations available from complexation with different metals offer a desirable diversity to probe receptors for reverse-turn recognition.

Original languageEnglish
Pages (from-to)99-110
Number of pages12
JournalChemical Biology and Drug Design
Issue number2
StatePublished - Feb 2007


  • Density functional theory
  • Pentaazacrown
  • Peptidomimetics
  • Principal component analysis
  • Privileged structure
  • Protein-protein interaction
  • Reverse turn
  • Template design
  • Transition metal


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