Ranking ligand affinity for the DNA minor groove by experiment and simulation

Kitiyaporn Wittayanarakul, N.G. Anthony, Witcha Treesuwan, Supa Hannongbua, Hasan Alniss, A.I. Khalaf, C.J. Suckling, J.A. Parkinson, Simon P. Mackay, Royal Golden Jubilee Ph.D. Program (Funder), Thailand Research Fund (Funder), W.T. and EPSRC (Funder), Scottish Funding Council (Funder)

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Abstract

The structural and thermodynamic basis for the strength and selectivity of the interactions of minor-groove binders (MGBs) with DNA is not fully understood. In 2003 we reported the first example of a thiazole containing MGB that bound in a phase shifted pattern that spanned 6 base-pairs rather than the usual 4 (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and molecular dynamics, we have established that the flanking bases around the central 4 being read by the ligand have subtle effects on recognition. We have investigated the effect of these flanking sequences on binding and the reasons for the differences and established a computational method to rank ligand affinity against varying DNA sequences.
Original languageEnglish
Pages (from-to)376-680
Number of pages5
JournalMedicinal Chemistry Letters
Volume1
Issue number8
DOIs
Publication statusPublished - 30 Jul 2010

Keywords

  • ligand affinity
  • DNA minor groove
  • minor groove binders
  • DNA footprinting
  • NMR spectroscopy
  • isothermal titration calorimetry
  • molecular dynamics
  • experiment
  • simulation

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    Wittayanarakul, K., Anthony, N. G., Treesuwan, W., Hannongbua, S., Alniss, H., Khalaf, A. I., Suckling, C. J., Parkinson, J. A., Mackay, S. P., Royal Golden Jubilee Ph.D. Program (Funder), Thailand Research Fund (Funder), W.T. and EPSRC (Funder), & Scottish Funding Council (Funder) (2010). Ranking ligand affinity for the DNA minor groove by experiment and simulation. Medicinal Chemistry Letters, 1(8), 376-680. https://doi.org/10.1021/ml100047n