High Throughput in-silico Screening against Flexible Protein Receptors

Abstract

We report results for the in-silico screening of a database of 10000 flexible compounds against various crystal structures of the thymidine kinase receptor complexed with 10 known substrates. The ligands were docked using FlexScreen, a recently developed docking tool based on the stochastic tunneling method. We used a first-principle based scoring function. For rigid receptor conformations we find large deviations in the rank of the known inhibitors depending on the choice of receptor conformation. These data demonstrate that the failure to dock originates from the neglect of receptor degrees of freedom and is not attributable to deficiencies in the scoring function or the docking algorithm. We then performed a screen in which critical receptor sidechains were permitted to change their conformation and found improved scores for those inhibitors that did not dock well in any of the previous screens. Consequently, the consideration of receptor sidechain flexibility in all-atom FlexScreen improves the quality of the screening approach.