title: A platform for designing HIV integrase inhibitors. Part 2: a two-metal binding model as a potential mechanism of HIV integrase inhibitors.
abstract: We propose a two-metal binding model as a potential mechanism of chelating inhibitors against HIV integrase (HIV IN) represented by 2-hydroxy-3-heteroaryl acrylic acids (HHAAs). Potential inhibitors would bind to two metal ions in the active site of HIV IN to prevent human DNA from undergoing the integration reaction. Correlation of the results of metal (Mg(2+) and Mn(2+)) titration studies with HIV IN inhibition for a series of active and inactive compounds provides support for the model. Results suggest Mg(2+) is an essential cofactor for chelating inhibitors.
authors.affiliation: Shionogi Research Laboratories, Shionogi & Company, Ltd, Sagisu, Fukushima-ku, Osaka 553-0002, Japan. takashi.kawasuji@shionogi.co.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasuji
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fuji
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Yoshinaga
authors.forename: Akihiko
authors.initials: A
authors.lastname: Sato
authors.forename: Tamio
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Kiyama
mesh_terms: D000179:Acrylates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D019427:HIV Integrase / Q000737:chemistry* / Q000378:metabolism; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008274:Magnesium / Q000378:metabolism*; D008345:Manganese / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000179:Acrylates; D019380:Anti-HIV Agents; D002614:Chelating Agents; D019428:HIV Integrase Inhibitors; D008345:Manganese; D019427:HIV Integrase; D008274:Magnesium