title: Classification of ADAMTS binding sites: The first step toward selective ADAMTS7 inhibitors.
abstract: Genome-wide association studies identified ADAMTS7 as a risk locus for coronary artery disease. In carotid arteries of rats, neointima formation after balloon-mediated injury goes along with enhanced Adamts7 expression. Vice versa, Adamts7-deficient mice display reduced neointima formation following vascular injury. Although a causal link between ADAMTS7 and coronary artery disease remains to be proven, inhibition of ADAMTS7 represents a potential new target for intervention in this disease. ADAMTS7, a member of the 'a disintegrin and metalloproteinase with thrombospondin motifs' (ADAMTS) family of proteins, contains a catalytic zinc ion in the binding site of its metalloproteinase domain. The structure of ADAMTS7 and its inhibitors are unknown. In this study, we used in silico methods, including homology modeling and pharmacophore modeling, to analyze the ADAMTS7 metalloproteinase domain, particularly its binding site. The results revealed structural and sequence differences relative to the binding sites of the other ADAMTS proteins; these non-conserved regions represent potential binding regions for selective ADAMTS7 inhibitors. The main contribution of this study is the proposal of a pharmacophore for ADAMTS7. The characterization of the ADAMTS7 binding site and definition of a pharmacophore are the first step toward developing a new therapeutic target for coronary artery disease.
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Germany; University Heart Center Luebeck, 23562 Lübeck, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Müller
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636 München, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Technische Universität München, Lazarettstr. 36, 80636 München, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Kessler
authors.affiliation: Deutsches Herzzentrum München, Technische Universität München, Lazarettstr. 36, 80636 München, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Technische Universität München, Lazarettstr. 36, 80636 München, Germany.
authors.forename: Heribert
authors.initials: H
authors.lastname: Schunkert
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Germany; University Heart Center Luebeck, 23562 Lübeck, Germany. Electronic address: jeanette.erdmann@iieg.uni-luebeck.de.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Erdmann
authors.affiliation: Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Maria-Goeppert-Str. 1, 23562 Lübeck, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Lübeck/Kiel, Germany; University Heart Center Luebeck, 23562 Lübeck, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tennstedt
mesh_terms: D051722:ADAM Proteins / Q000737:chemistry* / Q000648:ultrastructure*; D000071118:ADAMTS7 Protein; D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000737:chemistry; D008956:Models, Chemical; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020539:Sequence Analysis, Protein / Q000379:methods*
chemical_list: D004791:Enzyme Inhibitors; D051722:ADAM Proteins; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human
keywords: ADAMTS binding sites; ADAMTS7; Coronary artery disease; In silico studies; Inhibitor; Pharmacophore