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Molecules 2017, 22(11), 1945; doi:10.3390/molecules22111945

Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors

Department of Cell and Molecular Biology, Uppsala University, Biomedical Centre (BMC), BOX 596, SE-751 24 Uppsala, Sweden
Centro Singular Investigación Quimica Biologica e Materiales Moleculares (CIQUS), Departamento de Quimica Orgánica, Facultade de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
Author to whom correspondence should be addressed.
Received: 20 October 2017 / Revised: 7 November 2017 / Accepted: 8 November 2017 / Published: 10 November 2017
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
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The four receptors that signal for adenosine, A1, A2A, A2B and A3 ARs, belong to the superfamily of G protein-coupled receptors (GPCRs). They mediate a number of (patho)physiological functions and have attracted the interest of the biopharmaceutical sector for decades as potential drug targets. The many crystal structures of the A2A, and lately the A1 ARs, allow for the use of advanced computational, structure-based ligand design methodologies. Over the last decade, we have assessed the efficient synthesis of novel ligands specifically addressed to each of the four ARs. We herein review and update the results of this program with particular focus on molecular dynamics (MD) and free energy perturbation (FEP) protocols. The first in silico mutagenesis on the A1AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A2AAR, we demonstrate how FEP simulations can distinguish the conformational selectivity of a recent series of partial agonists. These novel results are complemented with the revision of the first series of enantiospecific antagonists on the A2BAR, and the use of FEP as a tool for bioisosteric design on the A3AR. View Full-Text
Keywords: free energy perturbation (FEP); G protein-coupled receptors (GPCRs); molecular dynamics (MD) simulations; structure-based drug design (SBDD) free energy perturbation (FEP); G protein-coupled receptors (GPCRs); molecular dynamics (MD) simulations; structure-based drug design (SBDD)

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Jespers, W.; Oliveira, A.; Prieto-Díaz, R.; Majellaro, M.; Åqvist, J.; Sotelo, E.; Gutiérrez-de-Terán, H. Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors. Molecules 2017, 22, 1945.

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