Abstract
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.
Highlights
Adenosine is a purine nucleoside and a native chemical that is irreplaceable in the life cycle of living organisms
We examine the sensitivity of the predictions to the charge distribution in the pyrimidine ring by a CH group to yield a pyridine ring, depicted as Series 2 and 3, respectively, in the models and compare results from different molecular dynamics (MD) simulation sampling results from different molecular dynamics (MD) simulation sampling methods and free energy protocols, 54a8 force field [16] used in this work, as opposed to the Q simulation package [17] implementing i.e., the GROMOS simulation package [15] using the GROMOS 54a8 force field [16] used in this work, the OPLS3 force field [18,19], employed in the work of Azuaje et al [14]
We provide an exploration of the effect of the bioisosteric replacement of pyrimidine by pyridine on ligand binding affinities to the A3 receptor
Summary
Adenosine is a purine nucleoside and a native chemical that is irreplaceable in the life cycle of living organisms. Adenosine itself accumulates in the extracellular space during metabolic stress such as ischemia, hypoxia, cell damage or inflammation [1,2] and serves as an alarm molecule to report tissue damage. It simultaneously triggers a series of reactions responsible for tissue protection and maintaining homeostasis [3], via interaction with one of the four adenosine receptors, A1 , A2A , A2B and A3.
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