title: A novel nonpeptide HIV-1 protease inhibitor: elucidation of the binding mode and its application in the design of related analogs.
abstract: HIV-1 protease has been identified as a significant target enzyme in AIDS research. While numerous peptide-derived inhibitors have been described, the identification of a nonpeptide inhibitor remains an important goal. Using an HIV-1 protease mass screening technique, 4-hydroxy-3-(3-phenoxypropyl)-2H-1-benzopyran-2-one (1) was identified as a nonpeptide competitive inhibitor of the enzyme. Employing a Monte Carlo-based docking procedure, the coumarin was docked in the active site of the enzyme, revealing a binding mode that was later confirmed by the X-ray crystal analysis. Several analogs were prepared to test the binding interactions and improve the overall binding affinity. The most active compound in the study was 4,7-dihydroxy-3-[4-(2-methoxyphenyl)butyl]-2H-1-benzopyran-2-one (31).
authors.affiliation: Parke-Davis Pharmaceutical Research, Division of Warner Lambert, Ann Arbor, Michigan 48105-2430.
authors.forename: E A
authors.initials: EA
authors.lastname: Lunney
authors.forename: S E
authors.initials: SE
authors.lastname: Hagen
authors.forename: J M
authors.initials: JM
authors.lastname: Domagala
authors.forename: C
authors.initials: C
authors.lastname: Humblet
authors.forename: J
authors.initials: J
authors.lastname: Kosinski
authors.forename: B D
authors.initials: BD
authors.lastname: Tait
authors.forename: J S
authors.initials: JS
authors.lastname: Warmus
authors.forename: M
authors.initials: M
authors.lastname: Wilson
authors.forename: D
authors.initials: D
authors.lastname: Ferguson
authors.forename: D
authors.initials: D
authors.lastname: Hupe
mesh_terms: D015110:4-Hydroxycoumarins / Q000737:chemistry* / Q000378:metabolism; D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy; D001665:Binding Sites; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D009010:Monte Carlo Method; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation
chemical_list: D015110:4-Hydroxycoumarins; D003374:Coumarins; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; C061946:MVT 101; C088971:PD 099560; D016333:HIV Protease