title: Structure of a non-peptide inhibitor complexed with HIV-1 protease. Developing a cycle of structure-based drug design.
abstract: A stable, non-peptide inhibitor of the protease from type 1 human immunodeficiency virus has been developed, and the stereochemistry of binding defined through crystallographic three-dimensional structure determination. The initial compound, haloperidol, was discovered through computational screening of the Cambridge Structural Database using a shape complementarity algorithm. The subsequent modification is a non-peptidic lateral lead, which belongs to a family of compounds with well characterized pharmacological properties. This thioketal derivative of haloperidol and a halide counterion are bound within the enzyme active site in a mode distinct from the observed for peptide-based inhibitors. A variant of the protease cocrystallized with this inhibitor shows binding in the manner predicted during the initial computer-based search. The structures provide the context for subsequent synthetic modifications of the inhibitor.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448.
authors.forename: E
authors.initials: E
authors.lastname: Rutenber
authors.forename: E B
authors.initials: EB
authors.lastname: Fauman
authors.forename: R J
authors.initials: RJ
authors.lastname: Keenan
authors.forename: S
authors.initials: S
authors.lastname: Fong
authors.forename: P S
authors.initials: PS
authors.lastname: Furth
authors.forename: P R
authors.initials: PR
authors.lastname: Ortiz de Montellano
authors.forename: E
authors.initials: E
authors.lastname: Meng
authors.forename: I D
authors.initials: ID
authors.lastname: Kuntz
authors.forename: D L
authors.initials: DL
authors.lastname: DeCamp
authors.forename: R
authors.initials: R
authors.lastname: Salto
mesh_terms: D001665:Binding Sites; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology*; D008958:Models, Molecular; D015394:Molecular Structure; D014961:X-Ray Diffraction
chemical_list: D017320:HIV Protease Inhibitors; D016333:HIV Protease