title: Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
abstract: We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.
authors.affiliation: Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA. akghosh@purdue.edu
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: Bruno D
authors.initials: BD
authors.lastname: Chapsal
authors.forename: Garth L
authors.initials: GL
authors.lastname: Parham
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: Masayuki
authors.initials: M
authors.lastname: Amano
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D019943:Amino Acid Substitution; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014520:Urethane / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D008024:Ligands; D014520:Urethane; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1