2V22

REPLACE: A strategy for Iterative Design of Cyclin Binding Groove Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Replace: A Strategy for Iterative Design of Cyclin- Binding Groove Inhibitors

Andrews, M.J.Kontopidis, G.Mcinnes, C.Plater, A.Innes, L.Cowan, A.Jewsbury, P.Fischer, P.M.

(2006) Chembiochem 7: 1909

  • DOI: https://doi.org/10.1002/cbic.200600189
  • Primary Citation of Related Structures:  
    2UUE, 2V22

  • PubMed Abstract: 

    We describe a drug-design strategy termed REPLACE (REplacement with Partial Ligand Alternatives through Computational Enrichment) in which nonpeptidic surrogates for specific determinants of known peptide ligands are identified in silico by using a core peptide-bound protein structure as a design anchor. In the REPLACE application example, we present the effective replacement of two critical binding motifs in a lead protein-protein interaction inhibitor pentapeptide with more druglike phenyltriazole and diphenyl ether groups. These were identified through docking of fragment libraries into the volume of the cyclin-binding groove of CDK2/cyclin A vacated through truncation of the inhibitor peptide-binding determinants. Proof of concept for this strategy was obtained through the generation of potent peptide-small-molecule hybrids and by the confirmation of inhibitor-binding modes in X-ray crystal structures. This method therefore allows nonpeptide fragments to be identified without the requirement for a high-sensitivity binding assay and should be generally applicable in replacing amino acids as individual residues or groups in peptide inhibitors to generate pharmaceutically acceptable lead molecules.


  • Organizational Affiliation

    Cyclacel Limited, James Lindsay Place, Dundee, DD1 5JJ, UK. martin.andrews@glpg.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELL DIVISION PROTEIN KINASE 2
A, C
298Homo sapiensMutation(s): 0 
EC: 2.7.1.37
UniProt & NIH Common Fund Data Resources
Find proteins for P24941 (Homo sapiens)
Explore P24941 
Go to UniProtKB:  P24941
PHAROS:  P24941
GTEx:  ENSG00000123374 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP24941
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
CYCLIN-A2
B, D
259Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for P20248 (Homo sapiens)
Explore P20248 
Go to UniProtKB:  P20248
PHAROS:  P20248
GTEx:  ENSG00000145386 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP20248
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C35
Query on C35

Download Ideal Coordinates CCD File 
E [auth B],
F [auth D]
N~2~-{[1-(4-CHLOROPHENYL)-5-METHYL-1H-1,2,4-TRIAZOL-3-YL]CARBONYL}-N~5~-(DIAMINOMETHYLIDENE)-L-ORNITHYL-L-LEUCYL-L-ISOLEUCYL-4-FLUORO-L-PHENYLALANINAMIDE
C37 H51 Cl F N11 O5
KPJZLROHGAJEAN-WRTIUAHLSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
C35 PDBBind:  2V22 IC50: 4100 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.60 Å
  • R-Value Free: 0.277 
  • R-Value Work: 0.171 
  • R-Value Observed: 0.174 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.693α = 90
b = 113.571β = 90
c = 156.025γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-01-29
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2019-08-21
    Changes: Data collection, Derived calculations
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Other, Refinement description