title: A series of penicillin-derived C2-symmetric inhibitors of HIV-1 proteinase: structural and modeling studies.
abstract: The binding modes of a series of penicillin-derived C2 symmetric dimer inhibitors of HIV-1 proteinase were investigated by NMR, protein crystallography, and molecular modeling. The compounds were found to bind in a symmetrical fashion, tracing and S-shaped course through the active site, with good hydrophobic interactions in the S1/S1' and S2/S2' pockets and hydrogen bonding of inhibitor amide groups. Interactions with the catalytic aspartates appeared poor and the protein conformation was very similar to that seen in complexes with peptidomimetics, in spite of the major differences in ligand structure.
authors.affiliation: Protein Structure Group, Glaxo Group Research Limited, Greenford, Middlesex, United Kingdom.
authors.forename: A
authors.initials: A
authors.lastname: Wonacott
authors.forename: R
authors.initials: R
authors.lastname: Cooke
authors.forename: F R
authors.initials: FR
authors.lastname: Hayes
authors.forename: M M
authors.initials: MM
authors.lastname: Hann
authors.forename: H
authors.initials: H
authors.lastname: Jhoti
authors.forename: P
authors.initials: P
authors.lastname: McMeekin
authors.forename: A
authors.initials: A
authors.lastname: Mistry
authors.forename: P
authors.initials: P
authors.lastname: Murray-Rust
authors.forename: O M
authors.initials: OM
authors.lastname: Singh
authors.forename: M P
authors.initials: MP
authors.lastname: Weir
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003461:Crystallography; D016333:HIV Protease / Q000737:chemistry; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010406:Penicillins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D017320:HIV Protease Inhibitors; D010406:Penicillins; D016333:HIV Protease