Universiteit Leiden

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Research project

Molecular modelling

An emerging role for water molecules in GPCR drug design?

Gerard van Westen

More and more GPCR crystal structures are now being elucidated. These crystal structures facilitate the understanding of ligand binding, receptor functioning and much more. Like with a good camera, the higher the resolution the more we can see in crystal structures. Quite recently we helped in resolving the crystal structure of the adenosine A2A receptor (PDB: 4EIY), which had an unprecedented resolution of 1.8 Å (Liu et al, Science 337 (2012) 232-236). This structure showed several interesting facets, including a sodium ion binding site and many, many water molecules.

The role of these water molecules is not always evident. It has been estimated, however, that at least in 85% of all available crystal structures the ligand-protein interaction is bridged through a water molecule. So instead of thinking of proteins and ligands interacting in vacuum, we should rather interpret protein-water-ligand interactions as a general view of how drugs act.

Certain water molecules can become “trapped”, in for instance lipophilic areas of the binding site. Typically these water molecules are energetically unfavourable. In the figure the results of a WaterMap calculation are shown, in which hydration sites coloured in red represent unfavourable water sites (ΔG > 5 kcal/mol), whereas the ones in green are favourable. The ligand shown in red is ZM241385, an A2A receptor antagonist. Using the knowledge obtained from these calculations, more potent derivatives can be designed and synthesized that displace energetically unfavourable waters.

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