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.

几种药物通过调节多个靶标发挥其治疗作用。基于结构的方法对于鉴定具有所需多药理学特征的化合物具有广阔的前景。这些方法利用蛋白质结合位点的知识来识别立体电子互补配体。在设计过程中选择最合适的蛋白质构象至关重要，特别是对于多靶点药物设计而言，其中相同的配体必须容纳在多个结合袋中。本文中，我们重点介绍了目前可用于选择最适合多靶点药物设计的蛋白质构象的技术，比较了每种方法的潜在优势和局限性，并评论了它们的组合如何对多药理学药物设计有帮助。