title: Docking studies on alphavbeta3 integrin ligands: pharmacophore refinement and implications for drug design.
abstract: Starting from the first crystal structure of the extracellular segment of the alpha(v)beta(3) integrin receptor with a cyclic RGD ligand bound to the active site, structural models for the interactions of known ligands with the alpha(v)beta(3) integrin receptor were generated by automated computational docking. The obtained complexes were evaluated for their consistency with structure-activity relationships and site-directed mutagenesis data. A comparison between the calculated interaction free energies and the experimental biological activities was also made. All the possible interactions of the investigated compounds at the active site and the probable ligand binding conformations provide an improved basis for structure-based rational ligand design. Additionally, our docking results allow a further validation and refinement of the pharmacophore model previously postulated by us.
authors.affiliation: Institut für Organische Chemie und Biochemie, Technische Universität München, Lichtenbergstrasse 4, D-85747 Garching, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Kay-E
authors.initials: KE
authors.lastname: Gottschalk
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Horst
authors.initials: H
authors.lastname: Kessler
mesh_terms: D000465:Algorithms; D001569:Benzodiazepines / Q000138:chemical synthesis / Q000494:pharmacology; D003460:Crystallization; D018360:Crystallography, X-Ray; D015195:Drug Design; D006860:Hydrogen Bonding; D039302:Integrin alphaVbeta3 / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D016297:Mutagenesis, Site-Directed; D009842:Oligopeptides; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D039302:Integrin alphaVbeta3; D008024:Ligands; D009842:Oligopeptides; D001569:Benzodiazepines; C047981:arginyl-glycyl-aspartic acid