4ZPF

BACE1 in complex with 8-(3-((1-aminopropan-2-yl)oxy)benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.

Egbertson, M.McGaughey, G.B.Pitzenberger, S.M.Stauffer, S.R.Coburn, C.A.Stachel, S.J.Yang, W.Barrow, J.C.Neilson, L.A.McWherter, M.Perlow, D.Fahr, B.Munshi, S.Allison, T.J.Holloway, K.Selnick, H.G.Yang, Z.Swestock, J.Simon, A.J.Sankaranarayanan, S.Colussi, D.Tugusheva, K.Lai, M.T.Pietrak, B.Haugabook, S.Jin, L.Chen, I.W.Holahan, M.Stranieri-Michener, M.Cook, J.J.Vacca, J.Graham, S.L.

(2015) Bioorg Med Chem Lett 25: 4812-4819

  • DOI: https://doi.org/10.1016/j.bmcl.2015.06.082
  • Primary Citation of Related Structures:  
    4ZPE, 4ZPF, 4ZPG

  • PubMed Abstract: 

    The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.


  • Organizational Affiliation

    Medicinal Chemistry Department, WP14-2 Merck and Co., West Point, PA 19486, USA. Electronic address: melissaegbertson@gmail.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1405Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4QD
Query on 4QD

Download Ideal Coordinates CCD File 
B [auth A]8-(3-{[(2S)-1-aminopropan-2-yl]oxy}benzyl)-4-(cyclohexylamino)-1-(3-fluorophenyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one
C29 H38 F N5 O2
GJCCGBZILLQLCV-NRFANRHFSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
4QD Binding MOAD:  4ZPF IC50: 180 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.201 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.182 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.72α = 90
b = 127.403β = 90
c = 77.024γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
DENZOdata reduction
PDB_EXTRACTdata extraction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-08-05 
  • Deposition Author(s): Orth, P.

Revision History  (Full details and data files)

  • Version 1.0: 2015-08-05
    Type: Initial release
  • Version 1.1: 2015-10-28
    Changes: Database references