4X6M

FACTOR XIA IN COMPLEX WITH THE INHIBITOR 1-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-3-[2-(aminomethyl)-5-chlorobenzyl]urea


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Structure-based design of inhibitors of coagulation factor XIa with novel P1 moieties.

Pinto, D.J.Smallheer, J.M.Corte, J.R.Austin, E.J.Wang, C.Fang, T.Smith, L.M.Rossi, K.A.Rendina, A.R.Bozarth, J.M.Zhang, G.Wei, A.Ramamurthy, V.Sheriff, S.Myers, J.E.Morin, P.E.Luettgen, J.M.Seiffert, D.A.Quan, M.L.Wexler, R.R.

(2015) Bioorg Med Chem Lett 25: 1635-1642

  • DOI: https://doi.org/10.1016/j.bmcl.2015.01.028
  • Primary Citation of Related Structures:  
    4X6M, 4X6N, 4X6O, 4X6P

  • PubMed Abstract: 

    Compound 2 was previously identified as a potent inhibitor of factor XIa lacking oral bioavailability. A structure-based approach was used to design analogs of 2 with novel P1 moieties with good selectivity profiles and oral bioavailability. Further optimization of the P1 group led to the identification of a 4-chlorophenyltetrazole P1 analog, which when combined with further modifications to the linker and P2' group provided compound 32 with FXIa Ki=6.7 nM and modest oral exposure in dogs.


  • Organizational Affiliation

    Bristol-Myers Squibb Company, Research and Development, 311 Pennington-Rocky Hill Rd., Pennington, NJ 08534, United States. Electronic address: donald.pinto@bms.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XI, light chain244Homo sapiensMutation(s): 2 
Gene Names: F11
EC: 3.4.21.27
UniProt & NIH Common Fund Data Resources
Find proteins for P03951 (Homo sapiens)
Explore P03951 
Go to UniProtKB:  P03951
PHAROS:  P03951
GTEx:  ENSG00000088926 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03951
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3Y3
Query on 3Y3

Download Ideal Coordinates CCD File 
B [auth A]1-{(1S)-1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-1H-imidazol-2-yl]-2-phenylethyl}-3-[2-(aminomethyl)-5-chlorobenzyl]urea
C27 H26 Cl2 N8 O
PKKLAAQPYSEUAW-QFIPXVFZSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3Y3 BindingDB:  4X6M Ki: 5.8 (nM) from 1 assay(s)
Binding MOAD:  4X6M Ki: 5.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.40 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.9α = 90
b = 78.9β = 90
c = 106.4γ = 120
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-02-18 
  • Deposition Author(s): Wei, A.

Revision History  (Full details and data files)

  • Version 1.0: 2015-02-18
    Type: Initial release
  • Version 1.1: 2015-03-18
    Changes: Database references
  • Version 1.2: 2015-04-01
    Changes: Database references