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Are macamides TLR ligands?: a NMR and molecular modelling study

Author
Organization
Abstract
Macamides are key secondary metabolites from the Maca plant (L. meyenii Walpers), which is a herbaceous plant cultivated mainly in the central Andes. The plant is associated to energizing properties and general positive effects on health; however, the exact mechanisms involved are still unknown. Dried powder products made from the roots are marketed worldwide as dietary supplements. While a range of secondary metabolites were isolated from the plant, macamides and macaenes might be linked to the entopharmacological effects of the plant as they were shown to be ligands of GPCR receptors of the Endogenous Cannabinoid System. Structurally the macamides are N-alkyl-amides containing saturated or polyunsaturated lipid tails. Many Pathogen Associated Molecular Patterns (PAMPs), which are endogenous ligands of the receptors of innate immune system responsible for sensing pathogens, contain multiple lipid side chains such as bacterial lipopeptides and glycolipdis such as lipospolysacccharide, lipoarabinomannan or lipoteichioic acid. These lipids chains play a crucial role in the recognition of PAMPs by their cognate receptors. Based on the structural similarity between of the saturated lipid chains in macamides, we hypothesised that that macamides could be ligands of the Toll-like Receptors (TLR). Since pre-existing solution state conformations affect the thermodynamics and kinetics of potential receptor binding, we investigated the solution state conformation of macamides in solution state by NMR spectroscopy and found that there is a preferential conformation of this compound in solution involving the lipid tail folding back towards the aromatic head group. Based on the found long range NOE contacts we determined the preferred solution state structure of macamides. We used these conformations as well as unconstrained structures to dock macamides to known binding sites of TLR4 and TLR2 and obtained viable complexes formed between the macamides and TLR2 as well as TLR4. The obtained results encourage further biophysical investigations and in vitro call assays.
Keywords
macamide, immunestimulator, Maca, molecular modelling, NMR

Citation

Please use this url to cite or link to this publication:

MLA
Chain, Fernando Ezequiel, et al. “Are Macamides TLR Ligands?: A NMR and Molecular Modelling Study.” TOLL 2015 : Targeting Innate Immunity : Abstracts Book, 2015, pp. 99–99.
APA
Chain, F. E., Martins, J., & Fehér, K. (2015). Are macamides TLR ligands?: a NMR and molecular modelling study. In TOLL 2015 : targeting innate immunity : abstracts book (pp. 99–99). Marbella, Spain.
Chicago author-date
Chain, Fernando Ezequiel, José Martins, and Krisztina Fehér. 2015. “Are Macamides TLR Ligands?: A NMR and Molecular Modelling Study.” In TOLL 2015 : Targeting Innate Immunity : Abstracts Book, 99–99.
Chicago author-date (all authors)
Chain, Fernando Ezequiel, José Martins, and Krisztina Fehér. 2015. “Are Macamides TLR Ligands?: A NMR and Molecular Modelling Study.” In TOLL 2015 : Targeting Innate Immunity : Abstracts Book, 99–99.
Vancouver
1.
Chain FE, Martins J, Fehér K. Are macamides TLR ligands?: a NMR and molecular modelling study. In: TOLL 2015 : targeting innate immunity : abstracts book. 2015. p. 99–99.
IEEE
[1]
F. E. Chain, J. Martins, and K. Fehér, “Are macamides TLR ligands?: a NMR and molecular modelling study,” in TOLL 2015 : targeting innate immunity : abstracts book, Marbella, Spain, 2015, pp. 99–99.
@inproceedings{7060881,
  abstract     = {{Macamides are key secondary metabolites from the Maca plant (L. meyenii Walpers), which is a herbaceous plant cultivated mainly in the central Andes. The plant is associated to energizing properties and general positive effects on health; however, the exact mechanisms involved are still unknown. Dried powder products made from the roots are marketed worldwide as dietary supplements. While a range of secondary metabolites were isolated from the plant, macamides and macaenes might be linked to the entopharmacological effects of the plant as they were shown to be ligands of GPCR receptors of the Endogenous Cannabinoid System. 
Structurally the macamides are N-alkyl-amides containing saturated or polyunsaturated lipid tails. Many Pathogen Associated Molecular Patterns (PAMPs), which are endogenous ligands of the receptors of innate immune system responsible for sensing pathogens, contain multiple lipid side chains such as bacterial lipopeptides and glycolipdis such as lipospolysacccharide, lipoarabinomannan or lipoteichioic acid. These lipids chains play a crucial role in the recognition of PAMPs by their cognate receptors. Based on the structural similarity between of the saturated lipid chains in macamides, we hypothesised that that macamides could be ligands of the Toll-like Receptors (TLR).
Since pre-existing solution state conformations affect the thermodynamics and kinetics of potential receptor binding, we investigated the solution state conformation of macamides in solution state by NMR spectroscopy and found that there is a preferential conformation of this compound in solution involving the lipid tail folding back towards the aromatic head group. Based on the found long range NOE contacts we determined the preferred solution state structure of macamides. We used these conformations as well as unconstrained structures to dock macamides to known binding sites of TLR4 and TLR2 and obtained viable complexes formed between the macamides and TLR2 as well as TLR4. The obtained results encourage further biophysical investigations and in vitro call assays.}},
  author       = {{Chain, Fernando Ezequiel and Martins, José and Fehér, Krisztina}},
  booktitle    = {{TOLL 2015 : targeting innate immunity : abstracts book}},
  keywords     = {{macamide,immunestimulator,Maca,molecular modelling,NMR}},
  language     = {{eng}},
  location     = {{Marbella, Spain}},
  pages        = {{99--99}},
  title        = {{Are macamides TLR ligands?: a NMR and molecular modelling study}},
  year         = {{2015}},
}