title: 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.
authors.affiliation: Johann Wolfgang Goethe-Universität, Institut für Organische Chemie und Chemische Biologie, Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Weisel
authors.forename: Ewgenij
authors.initials: E
authors.lastname: Proschak
authors.forename: Jan M
authors.initials: JM
authors.lastname: Kriegl
authors.forename: Gisbert
authors.initials: G
authors.lastname: Schneider
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D016000:Cluster Analysis; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry*
chemical_list: D008024:Ligands; D011506:Proteins