Abstract
With the exponential increase in publicly available protein structures, the comparison of protein binding sites naturally emerged as a scientific topic to explain observations or generate hypotheses for ligand design, notably to predict ligand selectivity for on- and off-targets, explain polypharmacology, and design target-focused libraries. The current review summarizes the state-of-the-art computational methods applied to pocket detection and comparison as well as structural druggability estimates. The major strengths and weaknesses of current pocket descriptors, alignment methods, and similarity search algorithms are presented. Lastly, an exhaustive survey of both retrospective and prospective applications in diverse medicinal chemistry scenarios illustrates the capability of the existing methods and the hurdle that still needs to be overcome for more accurate predictions.