Selection of protein conformations for structure-based polypharmacology studies

Luca Pinzi, Fabiana Caporuscio, Giulio Rastelli
2018 Drug Discovery Today  
Teaser This review will focus on currently available methods for the selection of the most suitable protein conformations for multi-target structure-based drug design. Highlights  Structure-based approaches play a central role in polypharmacology drug design.  Similar protein conformations are able to accommodate similar ligands.  The use of selected protein conformations affects structure-based drug design results.  In silico approaches for protein conformation selection are presented. 
more » ... amples of protein conformation selection for structure-based drug design are reported. ABSTRACT 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 employ the 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 of paramount importance, especially for multi-target drug design in which the same ligand has to be accommodated in multiple binding pockets. Herein, we will focus on currently available techniques for the selection of the most suitable protein conformations for multi-target drug design, compare potential advantages and limitations of each method, and comment on how their combination could help in polypharmacology drug design.
doi:10.1016/j.drudis.2018.08.007 pmid:30099123 fatcat:wg2x3d6nk5budkn6iuc23hopbe