Abstract
Adenosine receptors are involved in many pathological conditions and are thus promising drug targets. However, developing drugs that target this GPCR subfamily is a challenging task. A number of drug candidates fail due to lack of selectivity which results in unwanted side effects. The extensive structural similarity of adenosine receptors complicates the design of selective ligands. The problem of selective targeting is a general concern in GPCRs, and in this respect adenosine receptors are a prototypical example. Here we use enhanced sampling simulations to decipher the determinants of selectivity of ligands in A2a and A1 adenosine receptors. Our model shows how small differences in the binding pocket and in the water network around the ligand can be leveraged to achieve selectivity.
Highlights
Adenosine receptors are Class A G-protein-coupled receptors (GPCRs) that are widely expressed in neurons, immune system cells, and vascular system.[1]
To elucidate the binding pose and the role of the interfacial water, 1 μs-long unbiased molecular dynamics simulations (MD) were run for human A1R and A2aR in complex with either ZM241385 or LUF5452 starting with the ligand bound to the binding site
The salt bridge at the opening of the orthosteric binding site of A1R and A2aR significantly influences the dynamical nature of the interaction between the receptor and ligands
Summary
Adenosine receptors are Class A G-protein-coupled receptors (GPCRs) that are widely expressed in neurons, immune system cells, and vascular system.[1]. The lack of differences in the pockets of the two receptors poses a real challenge for the design of selective ligands.[5]
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