The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations

Martínez, J. Daniel; Infantino, Angela S.; Valverde, Pablo; Diercks, Tammo; Delgado, Sandra; Reichardt, Niels-Christian; Ardá, Ana; Cañada, Francisco Javier; Oscarson, Stefan; Jiménez-Barbero, Jesús

doi:10.3390/ph13080179

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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

¹,

²,

¹,

¹,

¹,

Niels-Christian Reichardt

³,

Ana Ardá

¹,

Francisco Javier Cañada

^4,5

Stefan Oscarson

and

Jesús Jiménez-Barbero

^1,6,7,*

CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology park, Building 800, 48160 Derio, Spain

Centre for Synthesis and Chemical Biology, University College Dublin, Belfield, Dublin 4, Ireland

CIC biomaGUNE, Basque Research Technology Alliance, BRTA, Miramon Park, 20014 San Sebastian, Spain

⁴

Centro de Investigaciones Biológicas Margarita Salas, CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain

⁵

CIBER de Enfermedades Respiratorias (CIBERES), Avda Monforte de Lemos 3-5, 28029 Madrid, Spain

⁶

Ikerbasque, Basque Foundation for Science, 48009 Bilbao, Spain

⁷

Deptartment Organic Chemistry II, Faculty of Science and Technology, UPV-EHU, 48940 Leioa, Spain

Author to whom correspondence should be addressed.

Pharmaceuticals 2020, 13(8), 179; https://doi.org/10.3390/ph13080179

Received: 1 July 2020 / Revised: 29 July 2020 / Accepted: 1 August 2020 / Published: 4 August 2020

(This article belongs to the Special Issue Glycomimetics and Glycoconjugates in Drug Discovery)

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Abstract

Fluorinated glycomimetics are frequently employed to study and eventually modulate protein–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–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–receptor complexes present in solution. View Full-Text

Keywords: NMR; molecular recognition; glycans; lectin; STD-NMR; DC-SIGN; glycomimetics; CORCEMA; MD simulations; fluorinated carbohydrates

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MDPI and ACS Style

Martínez, J.D.; Infantino, A.S.; Valverde, P.; Diercks, T.; Delgado, S.; Reichardt, N.-C.; Ardá, A.; Cañada, F.J.; Oscarson, S.; Jiménez-Barbero, J. The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations. Pharmaceuticals 2020, 13, 179. https://doi.org/10.3390/ph13080179

AMA Style

Martínez JD, Infantino AS, Valverde P, Diercks T, Delgado S, Reichardt N-C, Ardá A, Cañada FJ, Oscarson S, Jiménez-Barbero J. The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations. Pharmaceuticals. 2020; 13(8):179. https://doi.org/10.3390/ph13080179

Chicago/Turabian Style

Martínez, J. D., Angela S. Infantino, Pablo Valverde, Tammo Diercks, Sandra Delgado, Niels-Christian Reichardt, Ana Ardá, Francisco J. Cañada, Stefan Oscarson, and Jesús Jiménez-Barbero. 2020. "The Interaction of Fluorinated Glycomimetics with DC-SIGN: Multiple Binding Modes Disentangled by the Combination of NMR Methods and MD Simulations" Pharmaceuticals 13, no. 8: 179. https://doi.org/10.3390/ph13080179

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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

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