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

Abstract

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.

Insight into the Interactions between Novel Coumarin Derivatives and Human A3 Adenosine Receptors

“…Lenzi et al [35] showed the presence of hydrophobic residues in the binding access site of the hA 3 AR, whereas in the binding pocket gate of the hA 2A AR, there are some ionic residues. [36] On the other hand, the hypothetical binding mode for compounds 11-13 in the hA 1 AR is more similar to the pose previously reported for compounds 1-10. The oxopropoxy group is located in the upper region, whereas the aryl ring is located in the bottom of the pocket in a similar region as the furan ring of the co-crystallized ligand ZM241385 in the 3EML hA 2A AR crystal structure (Figure 4 a).…”

Molecular Determinants of Selectivity and Efficacy at the Dopamine D3 Receptor

“…26 WaterMap calculations were performed on the crystal structure of D3R (Figure S2) and on representative frames from the D3R- and D2R- 2 MD trajectories (Figure 2c and d). …”

Docking performance of the glide program as evaluated on the Astex and DUD datasets: a complete set of glide SP results and selected results for a new scoring function integrating WaterMap and glide

“…To generate a WaterMap for each receptor, the ligand is removed, a molecular dynamics simulation is carried out, and regions of water density that substantially exceed bulk density are identified as quasilocalized water sites [22][23][24][25][26][27][28]. The free energy required to displace these waters is estimated from a modified version of inhomogeneous solvation theory (IHT) [29][30][31]; various computational benchmark calculations and comparison with experimental data have established that the IHT approximation is a reasonably good one.…”