Free-energy calculations for bioisosteric modifications of A3 adenosine receptor antagonists
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Título: | Free-energy calculations for bioisosteric modifications of A3 adenosine receptor antagonists |
Autor/a: | Jandova, Zuzana Jespers, Willem Gutiérrez de Terán, Hugo Sotelo Pérez, Eddy Oostenbrink, Chris |
Centro/Departamento: | Universidade de Santiago de Compostela. Centro de Investigación en Química Biolóxica e Materiais Moleculares Universidade de Santiago de Compostela. Departamento de Química Orgánica |
Palabras chave: | Adenosine receptor | Free energy calculations | Molecular dynamics simulations | Groningen Molecular Simulation packace (GROMOS) | |
Data: | 2019 |
Editor: | MDPI |
Cita bibliográfica: | Jandova, Z.; Jespers, W.; Sotelo, E.; Gutiérrez-de-Terán, H.; Oostenbrink, C. Free-Energy Calculations for Bioisosteric Modifications of A3 Adenosine Receptor Antagonists. Int. J. Mol. Sci. 2019, 20, 3499 |
Resumo: | Adenosine receptors are a family of G protein-coupled receptors with increased attention as drug targets on different indications. We investigate the thermodynamics of ligand binding to the A3 adenosine receptor subtype, focusing on a recently reported series of diarylacetamidopyridine inhibitors via molecular dynamics simulations. With a combined approach of thermodynamic integration and one-step perturbation, we characterize the impact of the charge distribution in a central heteroaromatic ring on the binding affinity prediction. Standard charge distributions according to the GROMOS force field yield values in good agreement with the experimental data and previous free energy calculations. Subsequently, we examine the thermodynamics of inhibitor binding in terms of the energetic and entropic contributions. The highest entropy penalties are found for inhibitors with methoxy substituents in meta position of the aryl groups. This bulky group restricts rotation of aromatic rings attached to the pyrimidine core which leads to two distinct poses of the ligand. Our predictions support the previously proposed binding pose for the o-methoxy ligand, yielding in this case a very good correlation with the experimentally measured affinities with deviations below 4 kJ/mol |
Versión do editor: | https://doi.org/10.3390/ijms20143499 |
URI: | http://hdl.handle.net/10347/21303 |
DOI: | 10.3390/ijms20143499 |
E-ISSN: | 1422-0067 |
Dereitos: | © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/) |
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