3FHE

Leukotriene A4 Hydrolase complexed with inhibitor N-[3-(4-benzylphenoxy)propyl]-N-methyl-beta-alanine.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.16 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Discovery of 4-[(2S)-2-{[4-(4-chlorophenoxy)phenoxy]methyl}-1-pyrrolidinyl]butanoic acid (DG-051) as a novel leukotriene A4 hydrolase inhibitor of leukotriene B4 biosynthesis.

Sandanayaka, V.Mamat, B.Mishra, R.K.Winger, J.Krohn, M.Zhou, L.M.Keyvan, M.Enache, L.Sullins, D.Onua, E.Zhang, J.Halldorsdottir, G.Sigthorsdottir, H.Thorlaksdottir, A.Sigthorsson, G.Thorsteinnsdottir, M.Davies, D.R.Stewart, L.J.Zembower, D.E.Andresson, T.Kiselyov, A.S.Singh, J.Gurney, M.E.

(2010) J Med Chem 53: 573-585

  • DOI: https://doi.org/10.1021/jm900838g
  • Primary Citation of Related Structures:  
    3FH5, 3FH7, 3FH8, 3FHE, 3FTZ, 3FUL

  • PubMed Abstract: 

    Both in-house human genetic and literature data have converged on the identification of leukotriene 4 hydrolase (LTA(4)H) as a key target for the treatment of cardiovascular disease. We combined fragment-based crystallography screening with an iterative medicinal chemistry effort to optimize inhibitors of LTA(4)H. Ligand efficiency was followed throughout our structure-activity studies. As applied within the context of LTA(4)H inhibitor design, the chemistry team was able to design a potent compound 20 (DG-051) (K(d) = 26 nM) with high aqueous solubility (>30 mg/mL) and high oral bioavailability (>80% across species) that is currently undergoing clinical evaluation for the treatment of myocardial infarction and stroke. The structural biology-chemistry interaction described in this paper provides a sound alternative to conventional screening techniques. This is the first example of a gene-to-clinic paradigm enabled by a fragment-based drug discovery effort.


  • Organizational Affiliation

    Medicinal Chemistry, deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Leukotriene A-4 hydrolase611Homo sapiensMutation(s): 0 
Gene Names: LTA4HLTA4
EC: 3.3.2.6
UniProt & NIH Common Fund Data Resources
Find proteins for P09960 (Homo sapiens)
Explore P09960 
Go to UniProtKB:  P09960
PHAROS:  P09960
GTEx:  ENSG00000111144 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP09960
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
28P
Query on 28P

Download Ideal Coordinates CCD File 
H [auth A]N-[3-(4-benzylphenoxy)propyl]-N-methyl-beta-alanine
C20 H25 N O3
HSXNVULMYZGNGF-UHFFFAOYSA-N
YB
Query on YB

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
F [auth A]
YTTERBIUM (III) ION
Yb
AWSFICBXMUKWSK-UHFFFAOYSA-N
IMD
Query on IMD

Download Ideal Coordinates CCD File 
G [auth A]IMIDAZOLE
C3 H5 N2
RAXXELZNTBOGNW-UHFFFAOYSA-O
ZN
Query on ZN

Download Ideal Coordinates CCD File 
B [auth A]ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
E [auth A]ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
28P BindingDB:  3FHE Ki: 3 (nM) from 1 assay(s)
Kd: min: 60, max: 350 (nM) from 3 assay(s)
IC50: min: 2.5, max: 49 (nM) from 3 assay(s)
PDBBind:  3FHE IC50: 2.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.16 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.164 
  • R-Value Observed: 0.166 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 77.911α = 90
b = 86.844β = 90
c = 99.318γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-01-05
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Structure summary, Version format compliance
  • Version 1.2: 2019-11-20
    Changes: Advisory, Derived calculations
  • Version 1.3: 2023-09-06
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-11-29
    Changes: Database references