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Title: N-(N-[2-(3,5-Difluorophenyl)acetyl]-(S)-alanyl)-(S)-phenylglycine tert-butyl ester (DAPT): an inhibitor of γ-secretase, revealing fine electronic and hydrogen-bonding features

The title compound, C{sub 23}H{sub 26}F{sub 2}N{sub 2}O{sub 4}, is a dipeptidic inhibitor of γ-secretase, one of the enzymes involved in Alzheimer’s dis@@ease. The mol@@ecule adopts a compact conformation, without intra@@molecular hydrogen bonds. In the crystal structure, one of the amide N atoms forms the only inter@@molecular N—H⋯O hydrogen bond; the second amide N atom does not form hydrogen bonds. High-resolution synchrotron diffraction data permitted the unequivocal location and refinement without restraints of all H atoms, and the identification of the characteristic shift of the amide H atom engaged in the hydrogen bond from its ideal position, resulting in a more linear hydrogen bond. Significant residual densities for bonding electrons were revealed after the usual SHELXL refinement, and modeling of these features as additional inter@@atomic scatterers (IAS) using the program PHENIX led to a significant decrease in the R factor from 0.0411 to 0.0325 and diminished the r.m.s. deviation level of noise in the final difference Fourier map from 0.063 to 0.037 e Å{sup −3}.
Authors:
;  [1] ;  [2] ;  [3] ;  [4] ;  [5]
  1. Peptides International Inc., 11621 Electron Drive, Louisville, KY 40299 (United States)
  2. Lawrence Berkeley National Laboratory, One Cyclotron Road, Building 64R0121, Berkeley, CA 94720 (United States)
  3. Basic Research Program, SAIC-Frederick Inc., Synchrotron Radiation Research Section, MCL, NCI, Argonne National Laboratory, Biosciences Division, Building 202, Argonne, IL 60439 (United States)
  4. Synchrotron Radiation Research Section, MCL, NCI, Argonne National Laboratory, Biosciences Division, Building 202, Argonne, IL 60439 (United States)
  5. (United States)
Publication Date:
OSTI Identifier:
22347678
Resource Type:
Journal Article
Resource Relation:
Journal Name: Acta Crystallographica. Section C, Crystal Structure Communications; Journal Volume: 66; Journal Issue: Pt 12; Other Information: PMCID: PMC3014104; PMID: 21123889; PUBLISHER-ID: mx3037; OAI: oai:pubmedcentral.nih.gov:3014104; Copyright (c) International Union of Crystallography 2010; This is an open-access article distributed under the terms described at http://journals.iucr.org/services/termsofuse.html.; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
Denmark
Language:
English
Subject:
75 CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY; ATOMS; BONDING; COMPACTS; CRYSTAL STRUCTURE; CRYSTALS; DENSITY; DIFFRACTION; ELECTRONS; HYDROGEN; NOISE; R FACTORS; RESOLUTION; SIMULATION; SYNCHROTRONS