title: Preorganization of the hydroxyethylene dipeptide isostere: the preferred conformation in solution resembles the conformation bound to BACE.
abstract: Conformational analysis in solution of beta-secretase inhibitors 1 and 2 by NMR spectroscopy reveals that the hydroxyethylene isostere, an apparently flexible fragment widely used as a scissile bond replacement in aspartic protease inhibitors, exists in one predominant conformation in solution. This preferred conformation is similar to that adopted by the hydroxyethylene core of 1 in complex with beta-secretase and that adopted by hydroxyethylene cores of related compounds when bound to aspartic proteases, indicating that this structural unit is preorganized in solution.
authors.affiliation: Discovery Chemistry Research and Technologies, Lilly Research Laboratories, Centro de Investigación Lilly, Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Vidal
authors.forename: David
authors.initials: D
authors.lastname: Timm
authors.forename: Howard
authors.initials: H
authors.lastname: Broughton
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.forename: José A
authors.initials: JA
authors.lastname: Martín
authors.forename: Alfonso
authors.initials: A
authors.lastname: Rivera-Sagredo
authors.forename: James R
authors.initials: JR
authors.lastname: McCarthy
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Shapiro
authors.forename: Juan F
authors.initials: JF
authors.lastname: Espinosa
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D018360:Crystallography, X-Ray; D004151:Dipeptides / Q000737:chemistry*; D010450:Endopeptidases / Q000737:chemistry*; D006801:Humans; D007930:Leucine / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry*; D012996:Solutions; D014633:Valine / Q000737:chemistry
chemical_list: D004151:Dipeptides; D011480:Protease Inhibitors; D012996:Solutions; D010649:Phenylalanine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D007930:Leucine; D014633:Valine