title: Identification of Interaction Hot Spots in Structures of Drug Targets on the Basis of Three-Dimensional Activity Cliff Information.
abstract: Activity cliffs are defined as pairs or groups of structurally similar or analogous compounds that share the same specific activity but have large differences in potency. Although activity cliffs are mostly studied in medicinal chemistry at the level of molecular graphs, they can also be assessed by comparing compound binding modes. If such three-dimensional activity cliffs (3D-cliffs) are studied on the basis of X-ray complex structures, experimental ligand-target interaction details can be taken into account. Rapid growth in the number of 3D-cliffs that can be derived from X-ray complex structures has made it possible to identify targets for which a substantial body of 3D-cliff information is available. Activity cliffs are typically studied to identify structure-activity relationship determinants and aid in compound optimization. However, 3D-cliff information can also be used to search for interaction hot spots and key residues, as reported herein. For six of seven drug targets for which more than 20 3D-cliffs were available, series of 3D-cliffs were identified that were consistently involved in interactions with different hot spots. These 3D-cliffs often encoded chemical modifications resulting in interactions that were characteristic of highly potent compounds but absent in weakly potent ones, thus providing information for structure-based design.
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113, Bonn, Germany.|Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
authors.forename: Norbert
authors.initials: N
authors.lastname: Furtmann
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113, Bonn, Germany.
authors.forename: Ye
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gütschow
authors.affiliation: Department of Life Science Informatics, B-IT, LIMES Program Unit Chemical Biology and Medicinal Chemistry, Rheinische Friedrich-Wilhelms-Universität, Dahlmannstr. 2, D-53113, Bonn, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bajorath
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry; D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000737:chemistry; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry; D015195:Drug Design; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000737:chemistry; D065427:Factor Xa Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D054730:Protein Interaction Domains and Motifs; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000991:Antithrombins; D002257:Carbonic Anhydrase Inhibitors; D065427:Factor Xa Inhibitors; D008024:Ligands; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D004851:Epoxide Hydrolases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D024402:Carbonic Anhydrase II; C043134:leukotriene A4 hydrolase
keywords: X-ray structures; compound activity data; interaction analysis; interaction hot spots; structure-based design; three-dimensional activity cliffs