Lately, protein-water interactions have gained interest in drug design projects. Replacing the “right” water molecule can lead to a significant increase in potency. A number of programs have become available to predict the best water molecule to target as well as its contribution to potency. However, the ability of these tools to predict X-ray water positions and explain SAR has not been evaluated in a comprehensive study using the same set of protein-ligand complexes.<br/>Here, we present an evaluation of different water prediction programs, which can be used for placing as well as scoring water molecules. Special focus has been put on the comparability of the results from the different programs. Therefore, an automated procedure has been implemented to compare these results. The consistency of the programs results with experimental ones has been analysed in three aspects: (1) Precision in the placement of X-ray observed water molecules; (2) Re-creation of the observed X-ray water hydrogen bond network using “placed” water positions; and (3) Correlation between predicted water energies and the observed SAR.<br/>Water molecule placement and scoring has been performed on two protein-ligand systems: Bromodomains and Bruton’s Tyrosine Kinases. For both targets, matched ligand pairs were available that cause displacement of specific water molecules. Based on the observed changes in potency, the “happiness” of water molecules was assessed and compared to the predicted energies as calculated by each program. Additionally, the ability to forecast highly conserved water molecules not easily displaced by ligand modifications was determined. X-ray water molecules can be placed fairly accurately by the programs. However, the predicted energies and experimentally observed changes in potency very poorly correlate. Additionally, the results are highly variable between programs and even within the same program.

Conserved H<sub>2</sub>O in protein-ligand complexes: An evaluation of water prediction tools

253rd National Meeting (2017)

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Conserved H2O in protein-ligand complexes: An evaluation of water prediction tools

Conserved H₂O in protein-ligand complexes: An evaluation of water prediction tools