Recently, the study of protein-water interactions has gained interest in drug design projects. Targeting the “right” water molecule can lead to a significant increase in potency. To predict the best water molecule to target, a number of programs have become available. However, to date no comprehensive comparison of the ability of these tools to predict X-ray water positions and explain SAR has been done using the same set of protein-ligand complexes. Based on the outcome, models for water interaction and placement can be further improved.<br/><br/>In a first step, we evaluated water prediction programs on two sets of protein-ligand complexes, Bromodomains and Bruton’s Tyrosine Kinases. For both targets, matched ligand pairs were available that cause displacement of specific water molecules. Detailed results were collected with respect to water placement precision, re-creation of the observed hydrogen bond network and the correlation of predicted energies with respect to observed changes in potency. In a second step, using a large collection of well-resolved crystallographic water molecules as well as the outcome of the above studies, novel interaction geometries and a water placement strategy have been developed.

Water, water, everywhere...: Modeling water molecules in protein-ligand complexes

253rd National Meeting (2017)

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