Molecular mechanics study of transannular amine-ketone (N?C(DOUBLE BOND)O) interaction in medium-sized heterocycles

Griffith, Renate; Bremner, John B.; Titmuss, Stephen J.

doi:10.1002/(sici)1096-987x(19970715)18:9<1211::aid-jcc9>3.0.co;2-u

Cited by 5 publications

(3 citation statements)

References 32 publications

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“…13 Experimental values are split into two groups, corresponding to a short‐distance regime ( d CN ≤2.0 Å) and a long‐distance regime ( d CN ≥2.5 Å). From the theoretical side, all parameterization using standard force fields have been unsuccessful so far 6a. 9d Ad hoc empirical corrections were necessary to reproduce approximately molecular structures of cryptopine and clivorine, excluding any transferable parameters 6a.…”

Section: Introductionmentioning

confidence: 99%

“…From the theoretical side, all parameterization using standard force fields have been unsuccessful so far 6a. 9d Ad hoc empirical corrections were necessary to reproduce approximately molecular structures of cryptopine and clivorine, excluding any transferable parameters 6a. This, added to the extreme variability of the bond length, may suggest a more subtle bonding picture than the traditional n N (σ‐donor)→π * CO (acceptor) scheme 8.…”

Section: Introductionmentioning

confidence: 99%

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Unusual Bond Formation in Aspartic Protease Inhibitors: A Theoretical Study

Pilmé

Berthoumieux

Robert

et al. 2007

Chemistry A European J

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The origin of the formation of the weak bond N|C...O involved in an original class of aspartic protease inhibitors was investigated by means of the electron localization function (ELF) and explicitly correlated wave-function (MRCI) analysis. The distance between the electrophilic C and the nucleophilic N centers appears to be controlled directly by the polarity and proticity of the medium. In light of these investigations, an unusual dative N-C bonding picture was characterized. Formation of this bond is driven by the enhancement of the ionic contribution C(+)-O(-) induced mainly by the polarization effect of the near N lone pair, and to a lesser extent by a weak charge delocalization N-->CO. Although the main role of the solvating environment is to stabilize the ionic configuration, the protic solvent can enhance the C(+)-O(-) configuration through a slight but cumulative charge transfer towards water molecules in the short N-C distance regime. Our revisited bond scheme suggests the possible tuning of the N-CO interaction in the design of specific inhibitors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unusual Bond Formation in Aspartic Protease Inhibitors: A Theoretical Study

Pilmé

Berthoumieux

Robert

et al. 2007

Chemistry A European J

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“…An accurate quantum level of theory is crucial to the correct description of the N···CO core interacting with the aspartyl dyad, due to the intrinsic complexity of this system. No accurate transferable force field parameters exist for the N···CO bond, , in particular because the stability of the N···CO is highly sensitive to the nature of the surrounding medium. ,− For instance, the N···CO bond is unstable in apolar-aprotic media, leaving the tertiary amine and the aldehyde groups essentially independent. The structure of a complex between HIV-1 PR and an AAP has not been reported yet.…”

Section: Introductionmentioning

confidence: 99%

Low Inhibiting Power of N···CO Based Peptidomimetic Compounds against HIV-1 Protease: Insights from a QM/MM Study

Garrec

Cascella

Röthlisberger

et al. 2010

J. Chem. Theory Comput.

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International audienceRecently, Hasserodt et al. proposed new HIV-1 drug candidates based on a weak N···CO interaction, designed to be a close transition state analog (Gautier et al. Bioorg. Med. Chem. 2006, 14, 3835−3847; Waibel et al. J. Bioorg. Med. Chem. 2009, 17, 3671−3679). They suggested that further improvement of these compounds could take advantage of computational approaches. In the present work, we propose an atomistic model based on a QM/MM description of the N···CO core embedded in an amino-aldehyde peptidic inhibitor. We focus on the existence of the N···CO interaction in the aqueous and enzymatic media. We show that the N···CO bond holds in water, while in the protein, there is a competition between the formation of the weak N···CO bond and the conservation of the hydrogen bond network around the structural water molecule W301 that is known to be crucial for the binding of both substrates and inhibitors. This competition hampers the inhibitor to provide strong stabilizing interactions with all the key parts of the protein at the same time. Our calculations indicate that this competition we observed in peptidic compounds might be avoided by the proper design of nonpeptidic ones, following a similar strategy to that for cyclic urea derivatives and the FDA approved drug Tipranavir. Hence, our results encourage further development of the nonpeptidic hydrazino-urea derivatives suggested recently by Hasserodt et al

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Spectroscopic and Theoretical Investigations of Monocyclic Dioximes and Dimethoximes with Six-, Eight-, and Ten-Membered Rings

Strenge

Rademacher²

1999

Eur. J. Org. Chem.

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The dioximes 4–6 and the dimethoximes 7–9, which contain the functional groups in opposite positions of a six‐, eight‐, or ten‐membered ring, were synthesized. Their conformational properties and transannular interactions were investigated by spectroscopic (PE, 13C NMR) and theoretical (MMX, AM1, ab initio HF, and B3LYP) methods. While the cyclooctane derivatives 5 and 8 have conformations favourable for through‐space interactions of the π(CN) orbitals, in the other compounds no such interactions can be ascertained. Through‐space orbital interactions in the molecules with an eight‐membered ring lead to a splitting of the π(CN) MOs of 0.4 eV.

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Molecular mechanics study of transannular amine-ketone (N?C(DOUBLE BOND)O) interaction in medium-sized heterocycles

Cited by 5 publications

References 32 publications

Unusual Bond Formation in Aspartic Protease Inhibitors: A Theoretical Study

Unusual Bond Formation in Aspartic Protease Inhibitors: A Theoretical Study

Low Inhibiting Power of N···CO Based Peptidomimetic Compounds against HIV-1 Protease: Insights from a QM/MM Study

Spectroscopic and Theoretical Investigations of Monocyclic Dioximes and Dimethoximes with Six-, Eight-, and Ten-Membered Rings

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