Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 49, Issue 1, Pages 111-124Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm0507072
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Funding
- NIGMS NIH HHS [GM 53630, GM 68460] Funding Source: Medline
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Four residues making almost a complete 180 degrees turn in the direction of the peptide chain define a reverse turn, a common motif and recognition site in proteins. Cyclization between residues i + 1 and i + 2 positions are used to constrain a peptide to a reverse-turn conformation. A combined approach, cyclic tetrapeptides (CTPs) based on heterochiral dipeptides of chimeric amino acids, is evaluated as minimalist scaffolds for reverse-turn conformations. Cyclo-(D-Pro-L-Pro-D-Pro-L-Pro) has been studied with density functional theory (DFT) calculations and molecular dynamics simulations. The all-trans amide conformer was the most stable in vacuo, while the cis-trans-cis (ctct) or trans-cis-trans-cis (tctc) amide conformer was more favored in water due to its large dipole moment. Different conformations could be selectively stabilized by different sustitutions on the proline rings. Due to the small 12-membered ring and exocyclic constraints, conformational interconversions could only occur at high temperature. The presence of seven hydrogens on each ring that could be functionalized offers an overwhelming diversity to design molecules to probe receptors. The spatial relationships of C-alpha-C-beta vectors of reverse turns in proteins were subjected to principal component analysis of determination of the relative orientation of the C alpha-C beta vectors. Most reverse-turn structures could be mimicked effectively with a subset of CTP scaffolds with an root-mean-sqaure displacement (RMSD) of approximately 0.5 angstrom. Structural diversity of CTP scaffolds could be enhanced by the incorporation of proline analogues, such as azaproline (azPro) or pipecolic (Pip), azapipecolic (azPip), nipecotic (Nip), and isonipecotic (Inp) acids.
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