title: Rational design, synthesis, and crystallographic analysis of a hydroxyethylene-based HIV-1 protease inhibitor containing a heterocyclic P1'--P2' amide bond isostere.
abstract: The rational design and synthesis of a highly potent inhibitor of HIV-1 protease have been accomplished. The inhibitor, SB 206343, is based on a model derived from the structure of the MVT-101/HIV-1 protease complex and contains a 4(5)-acylimidazole ring as an isosteric replacement for the P1'--P2' amide bond. It is a competitive inhibitor with an apparent inhibition constant of 0.6 nM at pH 6.0. The three-dimensional structure of SB 206343 bound in the active site of HIV-1 protease has been determined at 2.3 A resolution by X-ray diffraction techniques and refined to a crystallographic discrepancy factor, R (= sigma parallel Fo magnitude of/Fc parallel/sigma magnitude of), of 0.194. The inhibitor is held in the enzyme by a set of hydrophobic and polar interactions. N-3 of the imidazole ring participates in a novel hydrogen-bonding interaction with the bound water molecule, demonstrating the effectiveness of the imidazole ring as an isosteric replacement for the P1'--P2' amide bond in hydroxyethylene-based HIV-1 protease inhibitors. Also present are hydrogen-bonding interactions between N-1 of the imidazole ring and the carbonyl of Gly-127 as well as between the imidazole acyl carbonyl oxygen and the amide nitrogen of Asp-129, exemplifying the peptidomimetic nature of the 4(5)-acylimidazole isostere. All of these interactions are in qualitative agreement with those predicted by the model.
authors.affiliation: Department of Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406.
authors.forename: S K
authors.initials: SK
authors.lastname: Thompson
authors.forename: K H
authors.initials: KH
authors.lastname: Murthy
authors.forename: B
authors.initials: B
authors.lastname: Zhao
authors.forename: E
authors.initials: E
authors.lastname: Winborne
authors.forename: D W
authors.initials: DW
authors.lastname: Green
authors.forename: S M
authors.initials: SM
authors.lastname: Fisher
authors.forename: R L
authors.initials: RL
authors.lastname: DesJarlais
authors.forename: T A
authors.initials: TA
authors.lastname: Tomaszek
authors.forename: T D
authors.initials: TD
authors.lastname: Meek
authors.forename: J G
authors.initials: JG
authors.lastname: Gleason
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D016333:HIV Protease / Q000187:drug effects / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D015203:Reproducibility of Results; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014633:Valine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000577:Amides; D017320:HIV Protease Inhibitors; D007093:Imidazoles; C089585:SB 206343; D016333:HIV Protease; D014633:Valine