5EGM

Development of a novel tricyclic class of potent and selective FIXa inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Development of a novel tricyclic class of potent and selective FIXa inhibitors.

Meng, D.Andre, P.Bateman, T.J.Berger, R.Chen, Y.H.Desai, K.Dewnani, S.Ellsworth, K.Feng, D.Geissler, W.M.Guo, L.Hruza, A.Jian, T.Li, H.Metzger, J.Parker, D.L.Reichert, P.Sherer, E.C.Smith, C.J.Sonatore, L.M.Tschirret-Guth, R.Wu, J.Xu, J.Zhang, T.Campeau, L.C.Orr, R.Poirier, M.McCabe-Dunn, J.Araki, K.Nishimura, T.Sakurada, I.Hirabayashi, T.Wood, H.B.

(2015) Bioorg Med Chem Lett 25: 5437-5443

  • DOI: https://doi.org/10.1016/j.bmcl.2015.07.078
  • Primary Citation of Related Structures:  
    5EGM

  • PubMed Abstract: 

    Using structure based drug design, a novel class of potent coagulation factor IXa (FIXa) inhibitors was designed and synthesized. High selectivity over FXa inhibition was achieved. Selected compounds were evaluated in rat IV/PO pharmacokinetic (PK) studies and demonstrated desirable oral PK profiles. Finally, the pharmacodynamics (PD) of this class of molecules were evaluated in thrombin generation assay (TGA) in Corn Trypsin Inhibitor (CTI) citrated human plasma and demonstrated characteristics of a FIXa inhibitor.


  • Organizational Affiliation

    Department of Discovery Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA. Electronic address: dongfang-meng@merck.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor IX235Homo sapiensMutation(s): 1 
Gene Names: F9
EC: 3.4.21.22
UniProt & NIH Common Fund Data Resources
Find proteins for P00740 (Homo sapiens)
Explore P00740 
Go to UniProtKB:  P00740
PHAROS:  P00740
GTEx:  ENSG00000101981 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00740
Sequence Annotations
Expand
  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor IX62Homo sapiensMutation(s): 0 
Gene Names: F9
EC: 3.4.21.22
UniProt & NIH Common Fund Data Resources
Find proteins for P00740 (Homo sapiens)
Explore P00740 
Go to UniProtKB:  P00740
PHAROS:  P00740
GTEx:  ENSG00000101981 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00740
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
5NY
Query on 5NY

Download Ideal Coordinates CCD File 
E [auth A]2-chloranyl-~{N}-[(7~{S})-2-methyl-7-phenyl-10-(1~{H}-1,2,3,4-tetrazol-5-yl)-8,9-dihydro-6~{H}-pyrido[1,2-a]indol-7-yl]-4-(1,2,4-triazol-4-yl)benzamide
C29 H24 Cl N9 O
TUCDMISJVGVBLL-GDLZYMKVSA-N
NHE
Query on NHE

Download Ideal Coordinates CCD File 
D [auth A]2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID
C8 H17 N O3 S
MKWKNSIESPFAQN-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
C [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
5NY Binding MOAD:  5EGM Ki: 2.4 (nM) from 1 assay(s)
BindingDB:  5EGM IC50: 2.38 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.84 Å
  • R-Value Free: 0.171 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 
  • Space Group: H 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 99.298α = 90
b = 99.298β = 90
c = 94.685γ = 120
Software Package:
Software NamePurpose
autoPROCdata scaling
XDSdata reduction
SCALAdata scaling
MOLREPphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-11-18
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Derived calculations, Refinement description
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Refinement description