<i>Cis</i>–<i>Trans</i> Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Laursen, Jonas S.; Engel-Andreasen, Jens; Fristrup, Peter; Harris, Pernille; Olsen, Christian A.

doi:10.1021/ja312532x

Cited by 129 publications

(135 citation statements)

References 86 publications

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“…12 This promotion of the Z-conformer, however, could not be definitively ascribed to the absence of the π* orbital and a loss of a putative n−π* aryl interaction. We therefore proceeded to increase the lone pair donor capability in the molecule by exchanging the carbonyl oxygen with sulfur.…”

Section: ■ Results and Discussionmentioning

confidence: 98%

Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

et al. 2015

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2-Substituted N-acyl-piperidine is a widespread and important structural motif, found in approximately 500 currently available structures, and present in nearly 30 pharmaceutically active compounds. Restricted rotation of the acyl substituent in such molecules can give rise to two distinct chemical environments. Here we demonstrate, using NMR studies and density functional theory modeling of the lowest energy structures of 5-acyl-6,7-dihydrothieno[3,2-c]pyridine derivatives, that the amide E:Z equilibrium is affected by non-covalent interactions between the amide oxygen and adjacent aromatic protons. Structural predictions were used to design molecules that promote either the E- or Z-amide conformation, enabling preparation of compounds with a tailored conformational ratio, as proven by NMR studies. Analysis of the available X-ray data of a variety of published N-acyl-piperidine-containing compounds further indicates that these molecules are also clustered in the two observed conformations. This finding emphasizes that directed conformational isomerism has significant implications for the design of both small molecules and larger amide-containing molecular architectures.

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Section: ■ Results and Discussionmentioning

confidence: 98%

Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

et al. 2015

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“…41 The rotation of the preceding-ω torsion angle has been both predicted and observed to alter the preferred χ 1 value, as well as pyramidalization of the backbone nitrogen (χ N ) and backbone carbonyl carbon (χ C ) atoms. 44,47,48 To quantify the effect ω has on these side-chain conformations, and to justify development of a backbone dependent rotamer library that includes this additional dihedral angle variability, we explored the ω-dependent energy landscapes.…”

Section: Resultsmentioning

confidence: 99%

A Rotamer Library to Enable Modeling and Design of Peptoid Foldamers

et al. 2014

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Peptoids are a family of synthetic oligomers composed of N-substituted glycine units. Along with other “foldamer” systems, peptoid oligomer sequences can be predictably designed to form a variety of stable secondary structures. It is not yet evident if foldamer design can be extended to reliably create tertiary structure features that mimic more complex biomolecular folds and functions. Computational modeling and prediction of peptoid conformations will likely play a critical role in enabling complex biomimetic designs. We introduce a computational approach to provide accurate conformational and energetic parameters for peptoid side chains needed for successful modeling and design. We find that peptoids can be described by a “rotamer” treatment, similar to that established for proteins, in which the peptoid side chains display rotational isomerism to populate discrete regions of the conformational landscape. Because of the insufficient number of solved peptoid structures, we have calculated the relative energies of side-chain conformational states to provide a backbone-dependent (BBD) rotamer library for a set of 54 different peptoid side chains. We evaluated two rotamer library development methods that employ quantum mechanics (QM) and/or molecular mechanics (MM) energy calculations to identify side-chain rotamers. We show by comparison to experimental peptoid structures that both methods provide an accurate prediction of peptoid side chain placements in folded peptoid oligomers and at protein interfaces. We have incorporated our peptoid rotamer libraries into ROSETTA, a molecular design package previously validated in the context of protein design and structure prediction.

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“…64 β-Peptoid monomer model compounds containing various side chains as well as thioamidation and trifluoroacetylation were synthesized and their conformational preferences analyzed by NMR spectroscopy, X-ray crystallography, and density functional theory (DFT) calculations. The NMR spectroscopic results demonstrated that the model compounds with varying side chains generally exhibit cis−trans isomerization equilibria in solution similar to their peptoid analogues (for examples, see Figure 7).…”

Section: β-Peptoidsmentioning

confidence: 99%

β-Peptoid Foldamers at Last

2015

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For a long time, peptides were considered unsuitable for drug development due to their inherently poor pharmacokinetic properties and proteolytic susceptibility. However, this paradigm has changed significantly in the past decade with the approval of numerous antibodies and proteins as drugs. In parallel, research in the field of synthetic molecules that are able to mimic or complement folding patterns exhibited by biopolymers, but are not recognized by proteases, have received considerable attention as well. Such entities were coined "foldamers" by Professor Gellman in an Account published in this journal in the late 1990s. Oligomers of N-alkylated 3-aminopropionic acid residues have been called β-peptoids due to their structural similarity to β-peptides and peptoids (N-alkylglycines), respectively. Because bona fide foldamer behavior has been demonstrated for both parent architectures, we wondered if the β-peptoids could serve as a successful addition to the known ensemble of peptidomimetic foldamers. When we entered this field, only the seminal description of libraries of β-peptoid dimers and trimers by Hamper et al. had been published a number of years earlier [ J. Org. Chem. 1998 , 63 , 708 ]. Perhaps somewhat naïvely in retrospect, we envisioned that elongation of chain length combined with introduction of bulky α-chiral side chains would deliver folded structures as reported for the α-peptoid counterparts. Initially, we, and others, were unsucessful in obtaining stable secondary structures of β-peptoid oligomers, and instead, these residues were either incorporated in cyclic structures or in combination with other types of residues to give peptidomimetic constructs with heterogeneous backbones. Amphiphilic architectures with various membrane-targeting activities, such as mimics of antimicrobial peptides or cell-penetrating peptides, have thus been particularly successful. Introduction of β-peptoid residues in histone deacetylase inhibitors mimicking nonribosomal cyclotetrapeptides have also been reported. In the present Account, we will sketch the scientific journey that ultimately delivered robustly folded β-peptoid oligomers. Contributions involving biological evaluation of peptidomimetic constructs containing β-peptoid residues, as mentioned above, which were investigated leading up to these recently reported high-resolution helical structures, will thus be discussed. On the basis of the work described in this Account, we envision that β-peptoids will find future utility as peptidomimetics for biomedical investigation containing both heterogeneous and homogeneous backbones. The recent demonstration of control over the secondary structure of a homogeneous β-peptoid backbone now enables structure-based design of scaffolds with predictable display of desired functionalities in three dimensions.

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Cis–Trans Amide Bond Rotamers in β-Peptoids and Peptoids: Evaluation of Stereoelectronic Effects in Backbone and Side Chains

Cited by 129 publications

References 86 publications

Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

Modulation of Amide Bond Rotamers in 5-Acyl-6,7-dihydrothieno[3,2-c]pyridines

A Rotamer Library to Enable Modeling and Design of Peptoid Foldamers

β-Peptoid Foldamers at Last

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