title: Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions.
abstract: HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.
authors.affiliation: Laboratoire de Chimie Organique et Macromoléculaire, UMR CNRS 8009, Université de Lille 1, 59655 Villeneuve d'Ascq, France.
authors.forename: C
authors.initials: C
authors.lastname: Maurin
authors.forename: F
authors.initials: F
authors.lastname: Bailly
authors.forename: P
authors.initials: P
authors.lastname: Cotelle
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002109:Caffeic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002384:Catalysis; D004279:DNA, Viral / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019427:HIV Integrase / Q000187:drug effects / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007651:Keto Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009282:Naphthalenesulfonates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D009841:Oligonucleotides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010636:Phenols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D059808:Polyphenols; D013329:Structure-Activity Relationship; D013386:Succinates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016662:Virus Integration / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D002109:Caffeic Acids; D004279:DNA, Viral; D005419:Flavonoids; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D008024:Ligands; D009282:Naphthalenesulfonates; D009841:Oligonucleotides; D010455:Peptides; D010636:Phenols; D059808:Polyphenols; D013386:Succinates; D019427:HIV Integrase; C100435:chicoric acid