Molecular modelling studies of new potential human DNA polymerase α inhibitors

J Enzyme Inhib Med Chem. 2011 Apr;26(2):270-9. doi: 10.3109/14756366.2010.503609. Epub 2010 Oct 20.


The human polymerase α (pol α) is a promising target for the therapy of cancer e.g. of the skin. The authors recently built a homology model of the active site of human DNA pol α. This 3D model was now used for molecular modelling studies with eight novel analogues of 2-butylanilino-dATP, which is a highly selective nucleoside inhibitor of mammalian pol α. Our results suggest that a higher hydrophobicity of a carbohydrate side chain (pointing into a spacious hydrophobic cavity) may enhance the strength of the interaction with the target protein. Moreover, acyclic acyclovir-like derivatives outperformed those with a sugar-moiety, indicating that structural flexibility and higher conformational adaptability has a positive effect on the receptor affinity. Cytotoxicity tests confirmed our theoretical findings. Besides, one of our most promising compounds in the molecular modelling studies revealed high selectivity for the SCC-25 cell line derived from squamous cell carcinoma in man.

MeSH terms

  • Catalytic Domain
  • Cell Line, Tumor
  • Cells, Cultured
  • DNA Polymerase I / antagonists & inhibitors*
  • DNA Polymerase I / chemistry*
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular*
  • Molecular Dynamics Simulation*
  • Structure-Activity Relationship


  • DNA Polymerase I