title: Investigating the role of metal chelation in HIV-1 integrase strand transfer inhibitors.
abstract: HIV-1 integrase (IN) has been validated as an attractive target for the treatment of HIV/AIDS. Several studies have confirmed that the metal binding function is a crucial feature in many of the reported IN inhibitors. To provide new insights on the metal chelating mechanism of IN inhibitors, we prepared a series of metal complexes of two ligands (HL1 and HL2), designed as representative models of the clinically used compounds raltegravir and elvitegravir. Potentiometric measurements were conducted for HL2 in the presence of Mg(II), Mn(II), Co(II), and Zn(II) in order to delineate a metal speciation model. We also determined the X-ray structures of both of the ligands and of three representative metal complexes. Our results support the hypothesis that several selective strand transfer inhibitors preferentially chelate one cation in solution and that the metal complexes can interact with the active site of the enzyme.
authors: Dipartimento di Chimica Generale ed Inorganica, Chimica Analitica, Chimica Fisica, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
authors: Alessia
authors: A
authors: Bacchi
authors: Mauro
authors: M
authors: Carcelli
authors: Carlotta
authors: C
authors: Compari
authors: Emilia
authors: E
authors: Fisicaro
authors: Nicolino
authors: N
authors: Pala
authors: Gabriele
authors: G
authors: Rispoli
authors: Dominga
authors: D
authors: Rogolino
authors: Tino W
authors: TW
authors: Sanchez
authors: Mario
authors: M
authors: Sechi
authors: Valentina
authors: V
authors: Sinisi
authors: Nouri
authors: N
authors: Neamati
mesh_terms: D020134:Catalytic Domain; D002413:Cations, Divalent; D002614:Chelating Agents / Q000737:chemistry*; D003035:Cobalt / Q000737:chemistry; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry*; D018360:Crystallography, X-Ray; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D008024:Ligands; D008274:Magnesium / Q000737:chemistry; D008345:Manganese / Q000737:chemistry; D008958:Models, Molecular; D011199:Potentiometry; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry; D015363:Quinolones / Q000138:chemical synthesis / Q000737:chemistry; D000068898:Raltegravir Potassium; D015032:Zinc / Q000737:chemistry
chemical_list: D002413:Cations, Divalent; D002614:Chelating Agents; D056831:Coordination Complexes; D019428:HIV Integrase Inhibitors; D008024:Ligands; D011760:Pyrrolidinones; D015363:Quinolones; D003035:Cobalt; D008345:Manganese; D000068898:Raltegravir Potassium; C509700:elvitegravir; D019427:HIV Integrase; D008274:Magnesium; D015032:Zinc; C514801:p31 integrase protein, Human immunodeficiency virus 1