Tautomer Preference in PDB Complexes and its Impact on Structure-Based Drug Discovery

Tautomer enrichment is a key step of ligand preparation prior to virtual screening. In this paper, we have investigated how tautomer preference in various media (water, gas phase, and crystal) compares to tautomer preference at the active site of the protein by analyzing the different possible H-bonding contacts for a set of 13 tautomeric structures. In addition, we have explored the impact of four different protocols for the enumeration of tautomers in virtual screening by using Flap, Glide, and Gold as docking tools on seven targets of the DUD data set. Excluding targets in which the binding does not involve tautomeric atoms (HSP90, p38, and VEGFR2), we found that the average receiver operating characteristic curve enrichment at 10% was 0.25 (Gold), 0.24 (Glide), and 0.50 (Flap) by considering only tautomers predicted to be unstable in water versus 0.41 (Gold), 0.56 (Glide), 0.51 (Flap) by limiting the enumeration process only to the predicted most stable tautomer. The inclusion of all tautomers (stable and unstable) yielded slightly poorer results than considering only the most stable form in water.