title: Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
abstract: Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor complex 1 led to replacement of two amide bonds and a 10 pi-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure-activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC50 value 1.8 +/- 0.2 nM; CIC95 value 46 +/- 4 nM) in this series. The X-ray structure of protein-inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S2 subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.
authors.affiliation: Department of Chemistry, University of Illinois at Chicago 60607, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Ghosh
authors.forename: J F
authors.initials: JF
authors.lastname: Kincaid
authors.forename: D E
authors.initials: DE
authors.lastname: Walters
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: N C
authors.initials: NC
authors.lastname: Chaudhuri
authors.forename: W J
authors.initials: WJ
authors.lastname: Thompson
authors.forename: C
authors.initials: C
authors.lastname: Culberson
authors.forename: P M
authors.initials: PM
authors.lastname: Fitzgerald
authors.forename: H Y
authors.initials: HY
authors.lastname: Lee
authors.forename: S P
authors.initials: SP
authors.lastname: McKee
authors.forename: P M
authors.initials: PM
authors.lastname: Munson
authors.forename: T T
authors.initials: TT
authors.lastname: Duong
authors.forename: P L
authors.initials: PL
authors.lastname: Darke
authors.forename: J A
authors.initials: JA
authors.lastname: Zugay
authors.forename: W A
authors.initials: WA
authors.lastname: Schleif
authors.forename: M G
authors.initials: MG
authors.lastname: Axel
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.forename: J R
authors.initials: JR
authors.lastname: Huff
mesh_terms: D000595:Amino Acid Sequence; D001224:Aspartic Acid; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009904:Optical Rotation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D005663:Furans; D017320:HIV Protease Inhibitors; D008024:Ligands; D001224:Aspartic Acid; C018674:tetrahydrofuran; D016333:HIV Protease