title: Structure-based design of potent HIV-1 protease inhibitors with modified P1-biphenyl ligands: synthesis, biological evaluation, and enzyme-inhibitor X-ray structural studies.
abstract: We report the design, synthesis, X-ray structural studies, and biological evaluation of a novel series of HIV-1 protease inhibitors. We designed a variety of functionalized biphenyl derivatives to make enhanced van der Waals interactions in the S1 subsite of HIV-1 protease. These biphenyl derivatives were conveniently synthesized using a Suzuki-Miyaura cross-coupling reaction as the key step. We examined the potential of these functionalized biphenyl-derived P1 ligands in combination with 3-(S)-tetrahydrofuranyl urethane and bis-tetrahydrofuranyl urethane as the P2 ligands. Inhibitor 21e, with a 2-methoxy-1,1'-biphenyl derivative as P1 ligand and bis-THF as the P2 ligand, displayed the most potent enzyme inhibitory and antiviral activity. This inhibitor also exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray crystal structure of related Boc-derivative 17a-bound HIV-1 protease provided important molecular insight into the ligand-binding site interactions of the biphenyl core in the S1 subsite of HIV-1 protease.
authors.affiliation: †Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Arun K
authors.initials: AK
authors.lastname: Ghosh
authors.affiliation: †Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Xufen
authors.initials: X
authors.lastname: Yu
authors.affiliation: †Departments of Chemistry and Medicinal Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, United States.
authors.forename: Heather L
authors.initials: HL
authors.lastname: Osswald
authors.affiliation: ‡Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, United States.
authors.forename: Johnson
authors.initials: J
authors.lastname: Agniswamy
authors.affiliation: ‡Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, United States.
authors.forename: Yuan-Fang
authors.initials: YF
authors.lastname: Wang
authors.affiliation: §Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Amano
authors.affiliation: ‡Department of Biology, Molecular Basis of Disease, Georgia State University, Atlanta, Georgia 30303, United States.
authors.forename: Irene T
authors.initials: IT
authors.lastname: Weber
authors.affiliation: §Departments of Hematology and Infectious Diseases, Kumamoto University Graduate School of Medical and Pharmaceutical Sciences, Kumamoto 860-8556, Japan.|∥Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, United States.|⊥Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry*; D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D011487:Protein Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology*; D014520:Urethane / Q000737:chemistry
chemical_list: D001713:Biphenyl Compounds; D002219:Carbamates; D016333:HIV Protease; D017320:HIV Protease Inhibitors; D008024:Ligands; D013449:Sulfonamides; D014520:Urethane; C000601737:hexahydrofuro(2,3-b)furan-3-yl-(3-hydroxy-4-(N-isobutyl-4-methoxyphenylsulfonamido)-1-(2'-methoxy-(1,1'-biphenyl)-3-yl)butan-2-yl)carbamate; C010574:biphenyl; C514803:p16 protease, Human immunodeficiency virus 1