CHAPTER 4: Computational Structural Modeling to Discover PPI Modulators

Protein–protein interactions (PPIs) play a critical role in the regulation of all cellular functions. The common recognition of PPIs as vital units of signal transduction and highly attractive therapeutic targets has resulted in an urgent need for potent and selective PPI modulators, especially for proteins lacking enzymatic activity. However, despite the advances in high-throughput screening technologies and synthetic chemistry, the regulation of PPIs by low molecular weight compounds remains a challenge. The three-dimensional structures of individual proteins and protein–protein complexes provide an opportunity to guide and reinforce experimental approaches by the methods of computational molecular modeling. This chapter summarizes the cutting-edge computational tools and web resources that help to determine the PPI interface and allosteric binding sites on the protein surface and to discover new promising PPI modulators through structure-based virtual screening.