Form follows function: Shape analysis of protein cavities for receptor‐based drug design

Abstract Identification of potential ligand‐binding pockets is an initial step in receptor‐based drug design. While many geometric or energy‐based binding‐site prediction methods characterize the size and shape of protein cavities, few of them offer an estimate of the pocket's ability to bind small drug‐like molecules. Here, we present a shape‐based technique to examine binding‐site druggability from the crystal structure of a given protein target. The method includes the PocketPicker algorithm to determine putative binding‐site volumes for ligand‐interaction. Pocket shape descriptors were calculated for both known ligand binding sites and empty pockets and were then subjected to self‐organizing map clustering. Descriptors were calculated for structures derived from a database of representative drug‐protein complexes with experimentally determined binding affinities to characterize the “druggable pocketome”. The new method provides a means for selecting drug targets and potential ligand‐binding pockets based on structural considerations and addresses orphan binding sites.