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The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations
- Source :
- Pharmaceuticals, Pharmaceuticals, Vol 13, Iss 179, p 179 (2020), Volume 13, Issue 8
- Publication Year :
- 2020
-
Abstract
- Fluorinated glycomimetics are frequently employed to study and eventually modulate protein&ndash<br />glycan interactions. However, complex glycans and their glycomimetics may display multiple binding epitopes that enormously complicate the access to a complete picture of the protein&ndash<br />ligand complexes. We herein present a new methodology based on the synergic combination of experimental 19F-based saturation transfer difference (STD) NMR data with computational protocols, applied to analyze the interaction between DC-SIGN, a key lectin involved in inflammation and infection events with the trifluorinated glycomimetic of the trimannoside core, ubiquitous in human glycoproteins. A novel 2D-STD-TOCSYreF NMR experiment was employed to obtain the experimental STD NMR intensities, while the Complete Relaxation Matrix Analysis (CORCEMA-ST) was used to predict that expected for an ensemble of geometries extracted from extensive MD simulations. Then, an in-house built computer program was devised to find the ensemble of structures that provide the best fit between the theoretical and the observed STD data. Remarkably, the experimental STD profiles obtained for the ligand/DC-SIGN complex could not be satisfactorily explained by a single binding mode, but rather with a combination of different modes coexisting in solution. Therefore, the method provides a precise view of those ligand&ndash<br />receptor complexes present in solution.
- Subjects :
- Materials science
Pharmaceutical Science
lcsh:Medicine
lcsh:RS1-441
010402 general chemistry
01 natural sciences
DC-SIGN
Article
lcsh:Pharmacy and materia medica
Molecular recognition
Glycomimetic
Drug Discovery
Relaxation matrix
MD simulations
fluorinated carbohydrates
STD-NMR
010405 organic chemistry
lcsh:R
Ligand (biochemistry)
Nmr data
NMR
3. Good health
0104 chemical sciences
NMR, MOLECULAR RECOGNITION, FLUORINE, GLYCAN, LECTIN, DC-SIGN
Saturation transfer
Chemical physics
CORCEMA
glycomimetics
Molecular Medicine
glycans
lectin
molecular recognition
Subjects
Details
- ISSN :
- 14248247
- Database :
- OpenAIRE
- Journal :
- Pharmaceuticals
- Accession number :
- edsair.doi.dedup.....fe2ed27c4f5db11b106a8fd5abaffc2c
- Full Text :
- https://doi.org/10.3390/ph13080179