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Free-Energy Calculations for Bioisosteric Modifications of A(3) Adenosine Receptor Antagonists
Univ Nat Resources & Life Sci, Inst Mol Modeling & Simulat, A-1190 Vienna, Austria.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0002-4951-9220
Univ Santiago de Compostela, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain;Univ Santiago de Compostela, Fac Farm, Dept Quim Organ, Santiago De Compostela 15782, Spain.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.ORCID iD: 0000-0003-0459-3491
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2019 (English)In: International Journal of Molecular Sciences, ISSN 1422-0067, E-ISSN 1422-0067, Vol. 20, no 14, article id 3499Article in journal (Refereed) Published
Abstract [en]

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 A(3) 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.

Place, publisher, year, edition, pages
MDPI , 2019. Vol. 20, no 14, article id 3499
Keywords [en]
Adenosine receptor, free energy calculations, molecular dynamics simulations, Groningen Molecular Simulation packace (GROMOS)
National Category
Theoretical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-393635DOI: 10.3390/ijms20143499ISI: 000480449300123PubMedID: 31315296OAI: oai:DiVA.org:uu-393635DiVA, id: diva2:1354380
Available from: 2019-09-25 Created: 2019-09-25 Last updated: 2019-09-25Bibliographically approved

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Jespers, WillemGutiérrez-de-Terán, HugoOostenbrink, Chris
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