title: Connectivity and binding-site recognition: applications relevant to drug design.
abstract: Here, we describe a family of methods based on residue-residue connectivity for characterizing binding sites and apply variants of the method to various types of protein-ligand complexes including proteases, allosteric-binding sites, correctly and incorrectly docked poses, and inhibitors of protein-protein interactions. Residues within ligand-binding sites have about 25% more contact neighbors than surface residues in general; high-connectivity residues are found in contact with the ligand in 84% of all complexes studied. In addition, a k-means algorithm was developed that may be useful for identifying potential binding sites with no obvious geometric or connectivity features. The analysis was primarily carried out on 61 protein-ligand structures from the MEROPS protease database, 250 protein-ligand structures from the PDBSelect (25%), and 30 protein-protein complexes. Analysis of four proteases with crystal structures for multiple bound ligands has shown that residues with high connectivity tend to have less variable side-chain conformation. The relevance to drug design is discussed in terms of identifying allosteric-binding sites, distinguishing between alternative docked poses and designing protein interface inhibitors. Taken together, this data indicate that residue-residue connectivity is highly relevant to medicinal chemistry.
authors.affiliation: Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester CO4 3SQ, United Kingdom.
authors.forename: Christopher J R
authors.initials: CJ
authors.lastname: Illingworth
authors.forename: Paul D
authors.initials: PD
authors.lastname: Scott
authors.forename: Kevin E B
authors.initials: KE
authors.lastname: Parkes
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Snell
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Campbell
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Reynolds
mesh_terms: D000465:Algorithms; D000495:Allosteric Site; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D015195:Drug Design; D008024:Ligands; D010447:Peptide Hydrolases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D011506:Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D008024:Ligands; D011506:Proteins; D010447:Peptide Hydrolases