Evaluation of Different Virtual Screening Programs for Docking in a Charged Binding Pocket

Virtual screening of small molecules against a protein target often identifies the correct pose, but the ranking in terms of binding energy remains a difficult problem, resulting in unacceptable numbers of false positives and negatives. To investigate this problem, the performance of three docking programs, FRED, QXP/FLO, and GLIDE, along with their five different scoring functions, was evaluated with the engineered cavity in cytochrome c peroxidase (CCP). This small cavity is negatively charged and completely buried from solvent. A test set of 60 molecules, experimentally identified as 43 "binders" and 17 "non-binders", were tested with the CCP binding site. The docking methods' performance is quantified by the ROC curve and their reproduction of crystal poses. The effects from generation of different ligand tautomers and inclusion of water molecule in the cavity are also discussed.