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Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Computational Biology and Bioinformatics.
Univ Santiago Compostela, Fac Farm, Dept Quim Organ, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
Univ Santiago Compostela, Fac Farm, Dept Quim Organ, Ctr Singular Invest Quim Biol & Mat Mol CIQUS, Santiago De Compostela 15782, Spain..
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2017 (English)In: Molecules, ISSN 1420-3049, E-ISSN 1420-3049, Vol. 22, no 11, article id 1945Article in journal (Refereed) Published
Abstract [en]

The four receptors that signal for adenosine, A(1), A(2A), A(2B) and A(3) 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 A(2A), and lately the A(1) 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 A(1)AR here reported allows understanding the specificity and high affinity of the xanthine-antagonist 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX). On the A(2A)AR, 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 A(2B)AR, and the use of FEP as a tool for bioisosteric design on the A(3)AR.

Place, publisher, year, edition, pages
MDPI AG , 2017. Vol. 22, no 11, article id 1945
Keywords [en]
free energy perturbation (FEP), G protein-coupled receptors (GPCRs), molecular dynamics (MD) simulations, structure-based drug design (SBDD)
National Category
Biochemistry and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-344330DOI: 10.3390/molecules22111945ISI: 000416528400145OAI: oai:DiVA.org:uu-344330DiVA, id: diva2:1188808
Funder
Swedish Research Council, 521-2014-2118eSSENCE - An eScience CollaborationEuropean Regional Development Fund (ERDF)Available from: 2018-03-08 Created: 2018-03-08 Last updated: 2018-03-09Bibliographically approved

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