Over the past 5 years, it has become clear that the water structure in a protein active site plays a major role in controlling ligand binding.  A localized water structure can be generated via molecular dynamics simulations, for example using the WaterMap program.  We have recently developed a modified version of the Glide XP scoring function, which we have named Wscore, in which the positions and free energies of displacement of the WaterMap waters in the active site are integrated into the XP scoring function. Other enhancements of XP, such as improved treatment of strain energy, are incorporated into Wscore as well.  We will discuss the impact of the localized water structure on ligand binding and present results for docking accuracy and enrichment for a large data set containing many pharmaceutically interesting receptors and ligands. The incorporation of water structure significant improves the ability to discriminate false positives from known active compounds. Preliminary results discussing the use of Wscore in prospective applications for ongoing drug discovery projects will also be presented.

Water structure in protein active sites: Modeling localized water sites and their effect on protein-ligand binding free energies

248th National Meeting (2014)

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