RT Journal Article
T1 Structure-Based Design of Potent and Selective Ligands at the Four Adenosine Receptors
A1 Jespers, Willem
A1 Oliveira, Ana
A1 Prieto Díaz, Rubén
A1 Majellaro, María
A1 Åqvist, Johan
A1 Sotelo Pérez, Eddy
A1 Gutiérrez de Terán, Hugo
K1 Free energy perturbation (FEP)
K1 G protein-coupled receptors (GPCRs)
K1 Molecular dynamics (MD) simulations
K1 Structure-based drug design (SBDD)
AB 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
PB MDPI
YR 2017
FD 2017
LK http://hdl.handle.net/10347/23519
UL http://hdl.handle.net/10347/23519
LA eng
NO 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
NO This work was supported by: the Swedish Research Council (Grant 521-2014-2118); the Swedish strategic research program eSSENCE; the Consellería de Cultura, Educación e Ordenación Universitaria of the Galician Government: (grant: GPC2014/03), Centro Singular de Investigación de Galicia accreditation 2016–2019 (ED431G/09) and the European Regional Development Fund (ERDF)
DS Minerva
RD 28 abr 2026