RCSB PDB - 3UFL: Discovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advancement through Conformational Design for Maintenance of Ligand Binding Efficiency

 3UFL

Discovery of Pyrrolidine-based b-Secretase Inhibitors: Lead Advancement through Conformational Design for Maintenance of Ligand Binding Efficiency


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 508Click on this verticalbar to view details

This is version 1.1 of the entry. See complete history


Literature

Discovery of pyrrolidine-based beta-secretase inhibitors: Lead advancement through conformational design for maintenance of ligand binding efficiency.

Stachel, S.J.Steele, T.G.Petrocchi, A.Haugabook, S.J.McGaughey, G.Katharine Holloway, M.Allison, T.Munshi, S.Zuck, P.Colussi, D.Tugasheva, K.Wolfe, A.Graham, S.L.Vacca, J.P.

(2012) Bioorg Med Chem Lett 22: 240-244

  • DOI: https://doi.org/10.1016/j.bmcl.2011.11.024
  • Primary Citation of Related Structures:  
    3UFL

  • PubMed Abstract: 

    We have developed a novel series of pyrrolidine derived BACE-1 inhibitors. The potency of the weak initial lead structure was enhanced using library-based SAR methods. The series was then further advanced by rational design while maintaining a minimal ligand binding efficiency threshold. Ultimately, the co-crystal structure was obtained revealing that these inhibitors interacted with the enzyme in a unique fashion. In all, the potency of the series was enhanced by 4 orders of magnitude from the HTS lead with concomitant increases in physical properties needed for series advancement. The progression of these developments in a systematic fashion is described.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., PO Box 4, West Point, PA 19486, USA. shawn_stachel@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1389Homo 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
508
Query on 508

Download Ideal Coordinates CCD File 
B [auth A](1R,4'S)-3,4-dihydro-2H-spiro[naphthalene-1,3'-pyrrolidin]-4'-yl[(2S,4R)-2,4-diphenylpiperidin-1-yl]methanone
C31 H34 N2 O
MXPUWFOJTXJTTA-RNWXARPHSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
E [auth A],
F [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
508 PDBBind:  3UFL IC50: 150 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.668α = 90
b = 127.642β = 90
c = 76.846γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted 508Click on this verticalbar to view details

Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-01-18
    Type: Initial release
  • Version 1.1: 2024-10-30
    Changes: Data collection, Database references, Derived calculations, Structure summary