6UVY

BACE-1 in complex with compound #18


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.140 

wwPDB Validation   3D Report Full Report

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This is version 1.2 of the entry. See complete history


Literature

Preparation and biological evaluation of BACE1 inhibitors: Leveraging trans-cyclopropyl moieties as ligand efficient conformational constraints.

Winneroski, L.L.Erickson, J.A.Green, S.J.Lopez, J.E.Stout, S.L.Porter, W.J.Timm, D.E.Audia, J.E.Barberis, M.Beck, J.P.Boggs, L.N.Borders, A.R.Boyer, R.D.Brier, R.A.Hembre, E.J.Hendle, J.Garcia-Losada, P.Minguez, J.M.Mathes, B.M.May, P.C.Monk, S.A.Rankovic, Z.Shi, Y.Watson, B.M.Yang, Z.Mergott, D.J.

(2020) Bioorg Med Chem 28: 115194-115194

  • DOI: https://doi.org/10.1016/j.bmc.2019.115194
  • Primary Citation of Related Structures:  
    6UVP, 6UVV, 6UVY, 6UWP, 6UWV

  • PubMed Abstract: 

    Inhibition of BACE1 has become an important strategy in the quest for disease modifying agents to slow the progression of Alzheimer's disease. We previously reported the fragment-based discovery of LY2811376, the first BACE1 inhibitor reported to demonstrate robust reduction of human CSF Aβ in a Phase I clinical trial. We also reported on the discovery of LY2886721, a potent BACE1 inhibitor that reached phase 2 clinical trials. Herein we describe the preparation and structure activity relationships (SAR) of a series of BACE1 inhibitors utilizing trans-cyclopropyl moieties as conformational constraints. The design, details of the stereochemically complex organic synthesis, and biological activity of these BACE1 inhibitors is described.


  • Organizational Affiliation

    Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.


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
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
QJP (Subject of Investigation/LOI)
Query on QJP

Download Ideal Coordinates CCD File 
C [auth A],
H [auth B]
(1R,2R)-2-[(4aS,7aR)-2-amino-4a,5-dihydro-4H-furo[3,4-d][1,3]thiazin-7a(7H)-yl]-N-{[(1R,2R)-2-methylcyclopropyl]methyl}cyclopropane-1-carboxamide
C15 H23 N3 O2 S
FKPBYKKZZCOMKI-MIDHOLSSSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
G [auth A],
L [auth B],
M [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
I [auth B]
J [auth B]
D [auth A],
E [auth A],
F [auth A],
I [auth B],
J [auth B],
K [auth B]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
QJP Binding MOAD:  6UVY IC50: 990 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.71 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.140 
  • R-Value Observed: 0.140 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.507α = 90
b = 90.134β = 90
c = 131.306γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report

Currently 6UVY does not have a validation slider image.



Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2019-12-11
    Type: Initial release
  • Version 1.1: 2020-01-01
    Changes: Database references
  • Version 1.2: 2023-10-11
    Changes: Data collection, Database references, Refinement description