Binding site comparisons for target-centered drug discovery

Introduction: The success of binding site comparisons in drug discovery is based on the recognized fact that many different proteins have similar binding sites. Indeed, binding site comparisons have found many uses in drug development and have the potential to dramatically cut the cost and shorten the time necessary for the development of new drugs.

Areas covered: The authors review recent methods for comparing protein binding sites and their use in drug repurposing and polypharmacology. They examine emerging fields including the use of binding site comparisons in precision medicine, the prediction of structured water molecules, the search for targets of natural compounds, and their application in the development of protein-based drugs by loop modeling and for comparison of RNA binding sites.

Expert opinion: Binding site comparisons have produced many interesting results in drug development, but relatively little work has been done on protein–protein interaction sites, which are particularly relevant in view of the success of biological drugs. Growth of protein loop modeling for modulating biological drugs is anticipated. The fusion of currently distinct methods for the comparison of RNA and protein binding sites into a single comprehensive approach could allow the search for new selective ribosomal antibiotics and initiate pharmaceutical research into other nucleoproteins.