4PMM

The structure of TrkA kinase bound to the inhibitor N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-{4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl}acetamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Maximizing diversity from a kinase screen: identification of novel and selective pan-Trk inhibitors for chronic pain.

Stachel, S.J.Sanders, J.M.Henze, D.A.Rudd, M.T.Su, H.P.Li, Y.Nanda, K.K.Egbertson, M.S.Manley, P.J.Jones, K.L.Brnardic, E.J.Green, A.Grobler, J.A.Hanney, B.Leitl, M.Lai, M.T.Munshi, V.Murphy, D.Rickert, K.Riley, D.Krasowska-Zoladek, A.Daley, C.Zuck, P.Kane, S.A.Bilodeau, M.T.

(2014) J Med Chem 57: 5800-5816

  • DOI: https://doi.org/10.1021/jm5006429
  • Primary Citation of Related Structures:  
    4PMM, 4PMP, 4PMS, 4PMT

  • PubMed Abstract: 

    We have identified several series of small molecule inhibitors of TrkA with unique binding modes. The starting leads were chosen to maximize the structural and binding mode diversity derived from a high throughput screen of our internal compound collection. These leads were optimized for potency and selectivity employing a structure based drug design approach adhering to the principles of ligand efficiency to maximize binding affinity without overly relying on lipophilic interactions. This endeavor resulted in the identification of several small molecule pan-Trk inhibitor series that exhibit high selectivity for TrkA/B/C versus a diverse panel of kinases. We have also demonstrated efficacy in both inflammatory and neuropathic pain models upon oral dosing. Herein we describe the identification process, hit-to-lead progression, and binding profiles of these selective pan-Trk kinase inhibitors.


  • Organizational Affiliation

    Departments of Medicinal Chemistry, Biological Chemistry, Pain & Migraine, Molecular Systems, and Structural Biology, Merck Research Laboratories , P.O. Box 4, West Point, Pennsylvania 19486, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
High affinity nerve growth factor receptor291Homo sapiensMutation(s): 0 
Gene Names: NTRK1MTCTRKTRKA
EC: 2.7.10.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04629 (Homo sapiens)
Explore P04629 
Go to UniProtKB:  P04629
PHAROS:  P04629
GTEx:  ENSG00000198400 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04629
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
31V
Query on 31V

Download Ideal Coordinates CCD File 
B [auth A]N-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-2-{4-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-1H-1,2,3-triazol-1-yl}acetamide
C27 H26 N8 O2
FQGDIYVVDKJSNC-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
C [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
G [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
CL
Query on CL

Download Ideal Coordinates CCD File 
D [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
31V BindingDB:  4PMM Kd: 27 (nM) from 1 assay(s)
IC50: min: 47, max: 662 (nM) from 5 assay(s)
Binding MOAD:  4PMM Kd: 27 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.165 
  • R-Value Observed: 0.166 
  • Space Group: P 64
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 75.8α = 90
b = 75.8β = 90
c = 112.34γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
PDB_EXTRACTdata extraction
BUSTERrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-06-18 
  • Deposition Author(s): Su, H.P.

Revision History  (Full details and data files)

  • Version 1.0: 2014-06-18
    Type: Initial release
  • Version 1.1: 2014-10-01
    Changes: Database references
  • Version 1.2: 2015-02-25
    Changes: Derived calculations
  • Version 1.3: 2023-12-27
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description, Source and taxonomy