title: From ligand to complexes. Part 2. Remarks on human immunodeficiency virus type 1 integrase inhibition by beta-diketo acid metal complexes.
abstract: Previously, we synthesized a series of beta-diketo acid metal complexes as novel HIV-1 integrase (IN) inhibitors (J. Med. Chem. 2006, 46, 4248-4260). Herein, a further extension of this study is reported. First, detailed docking studies were performed in order to investigate the mode of binding in the active site of the free ligands and of their metal complexes. Second, a series of potentiometric measurements were conducted for two diketo acids chosen as model ligands, with Mn(2+) and Ca(2+), in order to outline a speciation model. Third, we designed and synthesized a new set of complexes with different stoichiometries and tested them in an in vitro assay specific for IN. Finally, we obtained the first X-ray structure of a metal complex with HIV-1 IN inhibition activity. Analysis of these results supports the hypothesis that the diketo acids could act as complexes and form complexes with the metal ions on the active site of the enzyme.
authors.affiliation: Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Dipartimento di Scienze Farmacologiche, Biologiche e Chimiche Applicate, Universita di Parma, V.le Usberti 17/A, Campus Universitario, 43100 Parma, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Bacchi
authors.forename: Mariano
authors.initials: M
authors.lastname: Biemmi
authors.forename: Mauro
authors.initials: M
authors.lastname: Carcelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Carta
authors.forename: Carlotta
authors.initials: C
authors.lastname: Compari
authors.forename: Emilia
authors.initials: E
authors.lastname: Fisicaro
authors.forename: Dominga
authors.initials: D
authors.lastname: Rogolino
authors.forename: Mario
authors.initials: M
authors.lastname: Sechi
authors.forename: Martin
authors.initials: M
authors.lastname: Sippel
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Sotriffer
authors.forename: Tino W
authors.initials: TW
authors.lastname: Sanchez
authors.forename: Nouri
authors.initials: N
authors.lastname: Neamati
mesh_terms: D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007651:Keto Acids / Q000737:chemistry*; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008024:Ligands; D009942:Organometallic Compounds; D019427:HIV Integrase