Several drugs exert their therapeutic effect through the modulation of multiple targets. Structure-based approaches hold great promise for identifying compounds with the desired polypharmacological profiles. These methods use knowledge of the protein binding sites to identify stereoelectronically complementary ligands. The selection of the most suitable protein conformations to be used in the design process is vital, especially for multitarget drug design in which the same ligand has to be accommodated in multiple binding pockets. Herein, we focus on currently available techniques for the selection of the most suitable protein conformations for multitarget drug design, compare the potential advantages and limitations of each method, and comment on how their combination could help in polypharmacology drug design.
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