2G1Q

crystal structure of KSP in complex with inhibitor 9h


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.234 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Kinesin spindle protein (KSP) inhibitors. Part 4: Structure-based design of 5-alkylamino-3,5-diaryl-4,5-dihydropyrazoles as potent, water-soluble inhibitors of the mitotic kinesin KSP.

Cox, C.D.Torrent, M.Breslin, M.J.Mariano, B.J.Whitman, D.B.Coleman, P.J.Buser, C.A.Walsh, E.S.Hamilton, K.Schaber, M.D.Lobell, R.B.Tao, W.South, V.J.Kohl, N.E.Yan, Y.Kuo, L.C.Prueksaritanont, T.Slaughter, D.E.Li, C.Mahan, E.Lu, B.Hartman, G.D.

(2006) Bioorg Med Chem Lett 16: 3175-3179

  • DOI: https://doi.org/10.1016/j.bmcl.2006.03.040
  • Primary Citation of Related Structures:  
    2G1Q

  • PubMed Abstract: 

    Molecular modeling in combination with X-ray crystallographic information was employed to identify a region of the kinesin spindle protein (KSP) binding site not fully utilized by our first generation inhibitors. We discovered that by appending a propylamine substituent at the C5 carbon of a dihydropyrazole core, we could effectively fill this unoccupied region of space and engage in a hydrogen-bonding interaction with the enzyme backbone. This change led to a second generation compound with increased potency, a 400-fold enhancement in aqueous solubility at pH 4, and improved dog pharmacokinetics relative to the first generation compound.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, Sumneytown Pike, West Point, PA 19486, USA. chris_cox@merck.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Kinesin-like protein KIF11
A, B
368Homo sapiensMutation(s): 0 
Gene Names: KIF11EG5KNSL1
UniProt & NIH Common Fund Data Resources
Find proteins for P52732 (Homo sapiens)
Explore P52732 
Go to UniProtKB:  P52732
PHAROS:  P52732
GTEx:  ENSG00000138160 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP52732
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ADP
Query on ADP

Download Ideal Coordinates CCD File 
D [auth A],
G [auth B]
ADENOSINE-5'-DIPHOSPHATE
C10 H15 N5 O10 P2
XTWYTFMLZFPYCI-KQYNXXCUSA-N
N9H
Query on N9H

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B]
(5S)-5-(3-AMINOPROPYL)-3-(2,5-DIFLUOROPHENYL)-N-ETHYL-5-PHENYL-4,5-DIHYDRO-1H-PYRAZOLE-1-CARBOXAMIDE
C21 H24 F2 N4 O
OQMVLDZJPRSNOG-NRFANRHFSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
C [auth A],
F [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
N9H PDBBind:  2G1Q IC50: 44 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.51 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.234 
  • R-Value Observed: 0.234 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.68α = 90
b = 79.64β = 90
c = 158.7γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
SCALEPACKdata scaling
CNSrefinement
HKL-2000data reduction
CNSphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2006-10-03 
  • Deposition Author(s): Yan, Y.

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-03
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-02-14
    Changes: Data collection, Database references, Derived calculations