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Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor

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Schrödinger, Inc., 120 West 45th Street, 17th Floor, New York, New York 10036
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Cite this: ACS Med. Chem. Lett. 2010, 1, 4, 160–164
Publication Date (Web):May 10, 2010
Copyright © 2010 American Chemical Society

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    Abstract Image

    A series of triazolylpurine analogues show interesting and unintuitive structure−activity relationships against the A2A adenosine receptor. As the 2-substituted aliphatic group is initially increased to methyl and isopropyl, there is a decrease in potency; however, extending the substituent to n-butyl and n-pentyl results in a significant gain in potency. This trend cannot be readily explained by ligand−receptor interactions, steric effects, or differences in ligand desolvation. Here, we show that a novel method for characterizing solvent thermodynamics in protein binding sites correctly predicts the trend in binding affinity for this series based on the differential water displacement patterns. In brief, small unfavorable substituents occupy a region in the A2A adenosine receptor binding site predicted to contain stable waters, while the longer favorable substituents extend to a region that contains several unstable waters. The predicted binding energies associated with displacing water within these hydration sites correlate well with the experimental activities.

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    Predicted relative binding free energy (ΔΔG), entropy (−TΔΔS), and enthalpy (ΔΔH) for WaterMap calculations on the series of triazolylpurine A2A adenosine receptor antagonists is available in the supporting information along with additional details about the docking and WaterMap scoring calculations. This material is available free of charge via the Internet at

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