Receptor flexibility for large-scale in silico ligand screens: chances and challenges

An important contribution to today's computer-aided drug design is the automated screening of large compound databases against structurally resolved protein receptors targets. The introduction of ligand flexibility has, by now, become a standardized procedure. In contrast, a general approach to treat target degrees of freedom is still to be found, a consequence of the extreme increase of computational complexity, which comes along with the relaxation of protein degrees of freedom. In this chapter, we discuss in some detail both benefits and present limitations of target flexibility for high-throughput in silico database screens. Among the benefits are an improved diversity of binding modes, which allows one to identify a wider class of drug candidates. The limitations are related to a diminishing docking accuracy and an increased number of false hits. Using the thymidine kinase receptor and ten known inhibitors as an example, we describe in detail how target flexibility was implemented and how it affected the screening performance.