From ligand to complexes. Part 2. Remarks on human immunodeficiency virus type 1 integrase inhibition by beta-diketo acid metal complexes.
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.
Bacchi
Alessia
A
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.
Biemmi
Mariano
M
Carcelli
Mauro
M
Carta
Fabrizio
F
Compari
Carlotta
C
Fisicaro
Emilia
E
Rogolino
Dominga
D
Sechi
Mario
M
Sippel
Martin
M
Sotriffer
Christoph A
CA
Sanchez
Tino W
TW
Neamati
Nouri
N
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
D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008024:Ligands; D009942:Organometallic Compounds; D019427:HIV Integrase