6BFD

BACE crystal structure with hydroxy pyrrolidine inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.173 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Optimization of Hydroxyethylamine Transition State Isosteres as Aspartic Protease Inhibitors by Exploiting Conformational Preferences.

Bueno, A.B.Agejas, J.Broughton, H.Dally, R.Durham, T.B.Espinosa, J.F.Gonzalez, R.Hahn, P.J.Marcos, A.Rodriguez, R.Sanz, G.Soriano, J.F.Timm, D.Vidal, P.Yang, H.C.McCarthy, J.R.

(2017) J Med Chem 60: 9807-9820

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b01304
  • Primary Citation of Related Structures:  
    6BFD, 6BFE, 6BFW, 6BFX

  • PubMed Abstract: 

    NMR conformational analysis of a hydroxyethylamine peptide isostere developed as an aspartic protease inhibitor shows that it is a flexible architecture. Cyclization to form pyrrolidines, piperidines, or morpholines results in a preorganization of the whole system in solution. The resulting conformation is similar to the conformation of the inhibitor in the active site of BACE-1. This entropic gain results in increased affinity for the enzyme when compared with the acyclic system. For morpholines 27 and 29, the combination of steric and electronic factors is exploited to orient substituents toward S1, S1', and S2' pockets both in the solution and in the bound states. These highly preorganized molecules proved to be the most potent compounds of the series. Additionally, the morpholines, unlike the pyrrolidine and piperidine analogues, have been found to be brain penetrant BACE-1 inhibitors.


  • Organizational Affiliation

    Lilly SA , Avenida de la Industria 30, 28108 Alcobendas, Madrid, Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
442Homo sapiensMutation(s): 0 
Gene Names: BACE1BACEKIAA1149
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.62 Å
  • R-Value Free: 0.196 
  • R-Value Work: 0.173 
  • R-Value Observed: 0.173 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.46α = 90
b = 89.41β = 90
c = 131.41γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEITdata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-11-15 
  • Deposition Author(s): Timm, D.E.

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-15
    Type: Initial release
  • Version 1.1: 2017-12-27
    Changes: Database references