Docking methods often use a molecular mechanics model to sample ligand poses that form optimal networks of polar and non-polar interactions with the receptor, largely neglecting solvation effects while sampling ligand poses.  To account for receptor and ligand desolvation, scoring functions incorporating solvation models are often used to rescore docked poses. This approach risks undersampling ligand poses in the regions of the receptor with the most favorable desolvation energies (or vice versa).A novel method is described, that uses the SZMAP solvent mapping tool to characterize the stable and unstable water volumes in the receptor. The shape of the unstable water volume is used as a virtual screening query, to search for ligands with shapes that should optimally desolvate the receptor.  This approach was validated using high-throughput screening data, to demonstrate both the importance of considering solvation, and the utility of this method for virtual screening in lead generation.

Using solvent-mapping calculations for virtual screening

244th National Meeting (2012)

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