Prediction of the best linear precursor in the synthesis of cyclotetrapeptides by molecular mechanic calculations

Cavelier, Florine; Pèpe, Gérard; Verducci, Jean; Siri, Didier; Jacquier, Robert

doi:10.1021/ja00049a021

Cited by 74 publications

(59 citation statements)

References 3 publications

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“…Prediction of the sequence best able to cyclize has been attempted using the GenMol programme [88], which identified H-AlaAib-Phe-D-Pro-OPh as the best linear precursor for making cyclo (Aib-Phe-D-Pro-Ala). In a real comparison test [89] for the synthesis of cyclo (ArgGly-Asp-Phg) on a Kaiser oxime resin, the linear precursor, Arg(Tos)-Gly-Asp(c-Hex)-Phg giving 75% cyclic monomer, 20% cyclic dimer, proved to be the best sequence.…”

Section: Cyclotripeptides All-l Cyclotripeptides With All α-mentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

416

241

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Constricting the peptide backbone into a more defined conformational form through cyclization is an activity evolved in nature and in synthetic work, the latter straddling only the most recent decades. The resulting conformational constraints increase the probability of an optimum response with bio-receptors. The purpose of this review is to highlight developments that have proved to be reasonably efficient in the macrocyclization of linear precursors into cyclic peptides and depsipeptides.

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Section: Cyclotripeptides All-l Cyclotripeptides With All α-mentioning

confidence: 99%

The cyclization of peptides and depsipeptides

Davies

2003

Journal of Peptide Science

416

241

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“…It has been pointed out that the factors that influence the ability of a precursor to cyclize are: Steric hindrance to ring closure, kinetic competition with the dimerization reaction, and the energy from the transition-state to the reaction product (cyclic peptide). [24]. Methodologies to predict the tendencies of peptides to undergo cyclization have been reported.…”

Section: Introductionmentioning

confidence: 99%

Modeling of peptides containing D-amino acids: implications on cyclization

Yongye

Giulianotti

et al. 2009

J Comput Aided Mol Des

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Cyclic peptides are therapeutically attractive due to their high bioavailability, potential selectivity, and scaffold novelty. Furthermore, the presence of D-residues induces conformational preferences not followed by peptides consisting of naturally abundant L-residues. Therefore, comprehending how amino acids induce turns in peptides, subsequently facilitating cyclization, is significant in peptide design. Here, we performed 20-ns explicit-solvent molecular dynamics simulations for three diastereomeric peptides with stereochemistries: LLLLL, LLLDL, and LDLDL. Experimentally LLLLL and LDLDL readily cyclize, whereas LLLDL cyclizes in low yield. Simulations at 310 K produced conformations with inter-terminal hydrogen bonds that correlated qualitatively with the experimental cyclization trend. Energies obtained for representative structures from quantum chemical (B3LYP/PCM/cc-pVTZ//HF/6-31G*) calculations predicted pseudo-cyclic and extended conformations as the most stable for LLLLL and LLLDL, respectively, in agreement with the experimental data. In contrast, the most stable conformer predicted for peptide LDLDL was not a pseudo-cyclic structure. Moreover, D-residues preferred the experimentally less populated alpha(L) rotamers even when simulations were performed at a higher temperature and with strategically selected starting conformations. Energies calculated with molecular mechanics were consistent only with peptide LLLLL. Thus, the conformational preferences obtained for the all L: -amino acid peptide were in agreement with the experimental observations. Moreover, refinement of the force field is expected to provide far-reaching conformational sampling of peptides containing D-residues to further develop force field-based conformational-searching methods.

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“…The Aoe amino acid in these peptides, which include chlamydocin [232], HC-toxin [233], trapoxin B [234], WF-3161 [235], and Cyl-2 [236], is thought to act as an irreversible histone deacetylase inhibitor, presumably by covalent attachment of the epoxide moiety within the enzyme active site [237]. This group of natural product peptides has garnered much attention as a result of this and other notable bioactivities [238].…”

Section: Noncoded Amino Acids With Elaborate Side-chainsmentioning

confidence: 99%