Increasing Diversity in In-silico Screening with Target Flexibility

We investigate the impact of receptor flexibility with the all-atom FlexScreen docking approach using the thymidine kinase (TK) receptor as a model system. We study the screening performance when selected side chains of the target are treated in a continously flexible fashion in a screen of a database of 10000 compounds, which contains ten known substrates for the TK receptor. While the binding modes of the known substrates are not significantly affected as a function of receptor flexibility the mean binding energies of the database screen initially drop rapidly with increasing receptor flexibility but saturate when the number of target degrees of freedom is increased further. We demonstrate a dramatically increased diversity of the screen as 40% newly selected ligands appear in the top 500 ligands of the screen when receptor flexibility is taken into consideration.

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