title: Design, synthesis, biological evaluation and X-ray structural studies of HIV-1 protease inhibitors containing substituted fused-tetrahydropyranyl tetrahydrofuran as P2-ligands.
abstract: Design, synthesis, biological and X-ray crystallographic studies of a series of potent HIV-1 protease inhibitors are described. Various polar functionalities have been incorporated on the tetrahydropyranyl-tetrahydrofuran-derived P2 ligand to interact with the backbone atoms in the S2-subsite. The majority of the inhibitors showed very potent enzyme inhibitory and antiviral activity. Two high-resolution X-ray structures of 30b- and 30j-bound HIV-1 protease provide insight into ligand-binding site interactions. In particular, the polar functionalities on the P2-ligand appear to form unique hydrogen bonds with Gly48 amide NH and amide carbonyl groups in the flap region.
authors.affiliation: Departments of Chemistry and Medicinal Chemistry, Purdue University, West Lafayette, IN 47907, USA. akghosh@purdue.edu.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Cuthbert D
authors.initials: CD
authors.lastname: Martyr
authors.forename: Luke A
authors.initials: LA
authors.lastname: Kassekert
authors.forename: Prasanth R
authors.initials: PR
authors.lastname: Nyalapatla
authors.forename: Melinda
authors.initials: M
authors.lastname: Steffey
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000737:chemistry*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D008024:Ligands; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry*
chemical_list: D000577:Amides; D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; D011714:Pyrans; C018674:tetrahydrofuran