RT Journal Article
T1 Free-energy calculations for bioisosteric modifications of A3 adenosine receptor antagonists
A1 Jandova, Zuzana
A1 Jespers, Willem
A1 Gutiérrez de Terán, Hugo
A1 Sotelo Pérez, Eddy
A1 Oostenbrink, Chris
K1 Adenosine receptor
K1 Free energy calculations
K1 Molecular dynamics simulations
K1 Groningen Molecular Simulation packace (GROMOS)
AB 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
PB MDPI
YR 2019
FD 2019
LK http://hdl.handle.net/10347/21303
UL http://hdl.handle.net/10347/21303
LA eng
NO 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
NO This research was funded by the Austrian Science Fund, through the doctoral program BiomolecularTechnology of Proteins (BioToP), grant number W1224Acknowledgments: W.J. and H.G.T. thank the Swedish National Infrastructure for Computing (SNIC) forproviding computational resources
DS Minerva
RD 9 jun 2026