Fluctuation analysis and accuracy of a large-scale in silico screen

Using a cascadic version of the stochastic tunneling method we perform an all-atom database screen over 186,000 flexible ligands of the NCI 3D database against the thymidine kinase receptor. By analyzing the errors in the binding energy we demonstrate how the cascadic technique is superior to conventional sequential docking techniques and how reliable results for the determination of the top-scoring ligands could be achieved. The substrate corresponding to the crystal structure used in the screen ranks in the upper 0.05% of the database, validating both docking methodology and the applicability of the scoring function to this substrate. Several high ranking ligands of the database display significant structural similarity with known substrates. A detailed analysis of the accuracy of the screening method is carried out, and its dependence on the flexibility of the ligand is quantified.