5TFT

Structure of cytochrome P450 2D6 (CYP2D6) BACE1 inhibitor complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.71 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Aminomethyl-Derived Beta Secretase (BACE1) Inhibitors: Engaging Gly230 without an Anilide Functionality.

Butler, C.R.Ogilvie, K.Martinez-Alsina, L.Barreiro, G.Beck, E.M.Nolan, C.E.Atchison, K.Benvenuti, E.Buzon, L.Doran, S.Gonzales, C.Helal, C.J.Hou, X.Hsu, M.H.Johnson, E.F.Lapham, K.Lanyon, L.Parris, K.O'Neill, B.T.Riddell, D.Robshaw, A.Vajdos, F.Brodney, M.A.

(2017) J Med Chem 60: 386-402

  • DOI: https://doi.org/10.1021/acs.jmedchem.6b01451
  • Primary Citation of Related Structures:  
    5T1U, 5T1W, 5TFT, 5TFU

  • PubMed Abstract: 

    A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and provides a potential metabolic site leading to the formation of an aniline, a structural motif of prospective safety concern. We report herein an alternative aminomethyl linker that delivers similar potency and improved brain penetration relative to the amide moiety. Optimization of this series identified analogues with an excellent balance of ADME properties and potency; however, potential drug-drug interactions (DDI) were predicted based on CYP 2D6 affinities. Generation and analysis of key BACE1 and CYP 2D6 crystal structures identified strategies to obviate the DDI liability, leading to compound 16, which exhibits robust in vivo efficacy as a BACE1 inhibitor.


  • Organizational Affiliation

    Molecular and Experimental Medicine, The Scripps Research Institute , 10550 Torrey Pines Road, La Jolla, California 92024, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cytochrome P450 2D6
A, B, C, D
479Homo sapiensMutation(s): 0 
Gene Names: CYP2D6CYP2DL1
EC: 1.14.14.1
UniProt & NIH Common Fund Data Resources
Find proteins for P10635 (Homo sapiens)
Explore P10635 
Go to UniProtKB:  P10635
PHAROS:  P10635
GTEx:  ENSG00000100197 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP10635
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
L [auth C],
O [auth D]
PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
P6U
Query on P6U

Download Ideal Coordinates CCD File 
H [auth A],
K [auth B],
N [auth C],
Q [auth D]
(4S)-4-[2,4-difluoro-5-({[1-(trifluoromethyl)cyclopropyl]amino}methyl)phenyl]-4-methyl-5,6-dihydro-4H-1,3-thiazin-2-amine
C16 H18 F5 N3 S
XKONRMXLBXCJAM-AWEZNQCLSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
J [auth B],
M [auth C],
P [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
P6U BindingDB:  5TFT IC50: 157 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.71 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.213 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 57.474α = 90
b = 192.563β = 90
c = 247.901γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United StatesGM031001

Revision History  (Full details and data files)

  • Version 1.0: 2017-01-11
    Type: Initial release
  • Version 1.1: 2017-01-25
    Changes: Database references
  • Version 1.2: 2017-09-27
    Changes: Author supporting evidence
  • Version 1.3: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Derived calculations, Refinement description