title: On the importance of composite protein multiple ligand interactions in protein pockets.
abstract: Conventional small molecule drug-discovery approaches target protein pockets. However, the limited number of geometrically distinct pockets leads to widespread promiscuity and deleterious side-effects. Here, the idea of COmposite protein LIGands (COLIG) that interact with each other as well as the protein within a single ligand binding pocket is examined. As a practical illustration, experimental evidence that E. coli Dihydrofolate reductase inhibitors are COLIGs is presented. Then, analysis of a non-redundant set of all holo PDB structures indicates that almost 47-76% of proteins (based on different sequence identity thresholds) can simultaneously bind multiple, interacting ligands in the same pocket. Moreover, most ligands that are either Singletons and COLIGs bind at the bottom of ligand binding pocket and occupy 30% and 43% of the volume of the bottom of the pocket. This suggests the use of COLIGs as a potential new class of small molecule drugs. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 950 Atlantic Drive, Atlanta, Georgia, 30332.
authors.forename: Sam
authors.identifier: 0000-0003-3223-1359
authors.initials: S
authors.lastname: Tonddast-Navaei
authors.affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 950 Atlantic Drive, Atlanta, Georgia, 30332.
authors.forename: Bharath
authors.initials: B
authors.lastname: Srinivasan
authors.affiliation: Center for the Study of Systems Biology, School of Biology, Georgia Institute of Technology, 950 Atlantic Drive, Atlanta, Georgia, 30332.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Skolnick
mesh_terms: D001665:Binding Sites; D055808:Drug Discovery; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology*; D004927:Escherichia coli Infections / Q000188:drug therapy; D005493:Folic Acid Antagonists / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry / Q000378:metabolism*
chemical_list: D005493:Folic Acid Antagonists; D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries; D013762:Tetrahydrofolate Dehydrogenase
keywords: COmposite protein LIGands; aromatic interactions; emergence of biochemical specificity; ligand-ligand versus ligand-protein interactions; pocket volume occupied by ligands