Conformational analysis of dipeptide mimetics

Gillespie, Paul; Cicariello, Janet; Olson, Gary L.

doi:10.1002/(sici)1097-0282(1997)43:3<191::aid-bip2>3.3.co;2-2

Cited by 28 publications

(42 citation statements)

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“…The aim of this study was similar to that proposed by Olson and colleagues (24). In studying peptide mimetics, it is often not feasible to evaluate a wide range of compounds, making it preferable to screen putative mimetics based on structural and conformational criteria to select candidates for synthesis and testing.…”

Section: Discussionmentioning

confidence: 60%

“…A range of well‐studied peptide bond isosteres was chosen from the literature (24,26). They were modelled with charged N‐ and C‐termini, to compare their structure−conformer profiles with those of natural, zwitterionic peptides.…”

Section: Methodsmentioning

confidence: 99%

“…Consequently, to explore these aspects, we investigated the extent to which certain peptide bond isosteres exist in aqueous solution with backbone torsions and other features that are important for molecular recognition of natural peptides by peptide transporters and peptidases. Dialanine (AA) (I) and trialanine (AAA) (XI) were used as model zwitterionic substrates and their conformers were compared with isosteres having the following backbone modifications: N ‐methyl amide (CONCH 3 ) (II), retroamide (NHCO) (III), thioamide (CSNH) (IV), olefin (HC=CH) (V), aminomethylene (CH 2 NH) (VI), ketoethylene (COCH 2 ) (VII), hydroxyethylene (CH(OH)CH 2 ) (VIII), ethylene (CH 2 CH 2 ) (IX) and trans C=C isostere (C=CH‐NH) (X) (10,11,23–26). The results provide important structural information with which to improve selection of isosteres for synthesis and testing as surrogates of small peptides.…”

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confidence: 99%

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Evaluation of the conformational propensities of peptide isosteres as a basis for selecting bioactive pseudopeptides

Gupta

Payne

2001

The Journal of Peptide Research

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Our aim was to compare the repertoires of conformers formed by the model zwitterionic peptides AA and AAA in aqueous solution with the conformational profiles of a range of their peptide isosteres, so as to facilitate selection of isosteres for synthesis and testing as biologically stable surrogates of bioactive di- and tripeptides. Comparisons were based upon the results of conformational analysis using a random search approach implemented within the SYBYL molecular modelling package, using zwitterionic molecules, simulated aqueous solvation using a dielectric constant of 80 and allowing all torsions to vary. For each compound, individual conformers were grouped on the basis of specific combinations of psi, phi and omega torsions and, using their energies, the aggregated percentage for each group was calculated using a Boltzmann distribution and displayed using a 3D pseudo Ramachandran plot relating percentage conformer to psi and phi torsions. Retroamide, N-methylamide and thioamide isosteres showed the best match to natural peptides and to the molecular recognition parameters defined for substrates of peptide transporters. The results should aid rational design of therapeutic agents in various areas, e.g. oral delivery of drugs by peptide transporters and of peptidase inhibitors. This approach may usefully be applied to various biochemical and pharmaceutical topics.

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Section: Discussionmentioning

confidence: 60%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Evaluation of the conformational propensities of peptide isosteres as a basis for selecting bioactive pseudopeptides

Gupta

Payne

2001

The Journal of Peptide Research

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“…The wealth of peptide structures that exhibit remarkable biology has traditionally inspired the peptide scientist to devise tools for deciphering the spatial requirements for their activity. Endeavoring to understand the relationships between conformation and peptide biology, the chemistry of peptide mimicry has produced various strategies for replicating different secondary structures 1–24. With the advent of combinatorial science,113–115 new templates have recently emerged that possess different attributes as tools for building libraries of small molecules that may serve as peptide mimics.…”

Section: Discussionmentioning

confidence: 99%

“…Multiple strategies are necessary for accomplishing this task effectively, because of the diverse spectrum of conformations that peptides can adopt by variations of the orientations of side‐chain and backbone atoms. Since the introduction of strategies for peptide mimicry,1–6 many innovative approaches have been used to accelerate the process from peptide to biologically active small molecule 7–24. Kindly asked to review our own work on the synthesis and analysis of new scaffolds for peptide mimicry, we are pleased to write about two strategies that we have pursued for generating peptide mimics.…”

Section: Introductionmentioning

confidence: 99%

Design, synthesis, and conformational analysis of azacycloalkane amino acids as conformationally constrained probes for mimicry of peptide secondary structures

2000

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Conformationally constrained amino acid and dipeptide units can serve in mimics of specific secondary structures for studying relationships between peptide conformation and biological activity. A variety of mimics are required to study systematically the structure–activity relationships in biologically relevant peptides. We present our efforts on the design, synthesis, and conformational analysis of a series of rigid surrogates of amino acid and dipeptide units for application within constrained peptide analogues, and for employment as inputs for combinatorial science. Conceived to be general and versatile, our methodology has delivered a variety of azacycloalkane and azabicycloalkane amino acids in enantiomerically pure form, via practical methods, from readily available and inexpensive starting materials. ©2000 John Wiley & Sons, Inc. Biopoly 55: 101–122, 2000

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The Correlation of Electrochemical Measurements and Molecular Junction Conductance Simulations in β‐Strand Peptides

Horsley

2015

Chemistry A European J

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Understanding the electronic properties of single peptides is not only of fundamental importance, but it is also paramount to the realization of peptide-based molecular electronic components. Electrochemical and theoretical studies are reported on two β-strand-based peptides, one with its backbone constrained with a triazole-containing tether introduced by Huisgen cycloaddition (peptide 1) and the other a direct linear analogue (peptide 2). Density functional theory (DFT) and non-equilibrium Green's function were used to investigate conductance in molecular junctions containing peptides 3 and 4 (analogues of 1 and 2). Although the peptides share a common β-strand conformation, they display vastly different electronic transport properties due to the presence (or absence) of the side-bridge constraint and the associated effect on backbone rigidity. These studies reveal that the electron transfer rate constants of 1 and 2, and the conductance calculated for 3 and 4, differ by approximately one order of magnitude, thus providing two distinctly different conductance states and what is essentially a molecular switch. A definitive correlation of electrochemical measurements and molecular junction conductance simulations is demonstrated using two different charge transfer techniques. This study furthers our understanding of the electronic properties of peptides at the molecular level, which provides an opportunity to fine-tune their molecular orbital energies through suitable structural manipulation.

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Conformational analysis of dipeptide mimetics

Cited by 28 publications

References 0 publications

Evaluation of the conformational propensities of peptide isosteres as a basis for selecting bioactive pseudopeptides

Evaluation of the conformational propensities of peptide isosteres as a basis for selecting bioactive pseudopeptides

Design, synthesis, and conformational analysis of azacycloalkane amino acids as conformationally constrained probes for mimicry of peptide secondary structures

The Correlation of Electrochemical Measurements and Molecular Junction Conductance Simulations in β‐Strand Peptides

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