Conformational analysis of dipeptide mimetics

Abstract

A compendium of compounds designed as dipeptide mimetics was collected from the literature. Conformational space available to these molecules was evaluated to obtain distance and torsion angle parameters to aid in selection of mimetics for specific target peptides or to explore diversity strategies. Conformations were searched using the RandomSearch algorithm in SYBYL. Data were collected for conformations of each molecule falling within 5 kcal/mol of the minimum. The distance between capping groups on the N‐ and C‐termini of the molecules was measured as well as the pseudotorsion angle about a virtual bond between these two points. Molecules are classified based on the torsion angle space occupied and range of distances spanned by the resulting conformations. A large percentage of the dipeptide mimetics studied here have redundant conformational properties. The distribution of distances for all molecules covers an overall range of 3–15 Å, the majority falling between 5–8 Å. The angles for the majority of the molecules cover a wide range of torsional space with essentially no gaps in the values they can occupy, although these molecules can be subdivided by the average distance spanned by the allowed conformations. A smaller group of molecules have torsion angles that are restricted to a range of ±60° about the cis position (0°). Representative examples of each group are shown. We conclude that despite the significant effort to devise unique molecular structures as dipeptide mimetics, there is a need for more conformationally restricted compounds to mimic specific peptide conformations, and to complement molecular diversity strategies. © 1997 John Wiley & Sons, Inc. Biopoly 43: 191–217, 1997

Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers

“…22 The models for the two N-Boc protected β-strand peptides show that the macrocyclic 5 is 0.42 Å shorter than its linear analogue 6 (from first to last carbonyl carbons, see Table S1). All other dimensions crucial to the characterization of a β-strand conformation, such as NH(i) to NH(i+1), CαH(i) to NH(i+1) and CβH 2 (i) to NH(i+1) distances, are comparable to literature values 23 (Tables S2 and S3). The models indicate that the backbone lengths of peptides 7 and 8 (from first to last carbonyl carbons, see Tables S4 and S5) are strikingly similar, differing by no more than 0.17 Å.…”

Ligands for κ-Opioid and ORL1 Receptors Identified from a Conformationally Constrained Peptide Combinatorial Library

“…The TFT used is ATA, which was designed as a ␤-turn inducer (28) and used in the synthesis of a cyclic peptide template for protein engineering (50). Further analysis on the conformational preferences of ATA has been performed by Floegel and Mutter (51) and Gillespie et al (52). We report here the screening of this library for binding at the three recombinant human opioid receptors (, ␦, or ) and ORL1 receptor.…”

“…3, which are all commercially available with the exception of AMTA, which was prepared as described by Ernest et al (28). Their features as dipeptide mimetics are discussed in Gillespie et al (52). From the turn-scan we obtained a series of peptide III-derived compounds with novel pharmacological characteristics.…”

Systematic Study of the Synthesis of Macrocyclic Dipeptide β-Turn Mimics Possessing 8-, 9-, and 10- Membered Rings by Ring-Closing Metathesis

“…For example, fused bicyclic systems, such as azabicyclo[X,Y,0]-alkanone amino acids 1-4, of varying ring sizes have been used as rigid dipeptide surrogates 7 that structurally constrain three contiguous dihedral angles, φ, ψ, and ω, of a -turn segment within the body of the heterocycle (Figure 1). Conformational analysis of bicyclic lactams 1-4 has demonstrated their propensity to favor type II and II′ -turns 8,9 contingent on their stereochemistry, as evident from X-ray diffractometry, IR, and NMR spectroscopy as well as theoretical calculations. 10 Because differences in the type II turn dihedral angle have been observed after variation of the ring sizes in these bicyclic mimics, application of sets of related azabicycloalkane amino acids has thus proven effective for studying the effect of turn geometry on the biological activity of native peptides.…”