A Structural View on Druggability

Innovative and druggable targets are needed to fill the pipelines of pharmaceutical industry and to reduce the failure rates in clinical trials. The majority of current drug targets are G protein-coupled receptors (GPCRs), nuclear receptors, ion channels, or enzymes like kinases and proteases. This chapter addresses the recent developments regarding druggability assessment. It overviews varying interpretation of the term "druggability" in the literature, followed by a description of computational concepts utilizing structural information of proteins as well as of experimental approaches to assess druggability for classical targets (e.g. enzymes and receptors) and targets involved in protein-protein interaction (PPIs). In principle, there are two different in silico approaches to develop druggability models: use of pocket descriptors in scoring functions to discriminate druggable from undruggable targets; and a prediction of the maximal affinity that a drug-like molecule could attain for a binding site.