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

Kitiyaporn Wittayanarakul; Nahoum G Anthony; Witcha Treesuwan; Supa Hannongbua; Hasan Alniss; Abedawn I Khalaf; Colin J Suckling; John A Parkinson; Simon P Mackay

doi:10.1021/ml100047n

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

ACS Med Chem Lett. 2010 Jul 30;1(8):376-80. doi: 10.1021/ml100047n. eCollection 2010 Nov 11.

Authors

Kitiyaporn Wittayanarakul¹, Nahoum G Anthony¹, Witcha Treesuwan², Supa Hannongbua², Hasan Alniss¹, Abedawn I Khalaf³, Colin J Suckling³, John A Parkinson³, Simon P Mackay¹

Affiliations

¹ Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, United Kingdom.
² Chemistry Department and Center of Nanotechnology, Kasetsart University, Bangkok 10900, Thailand.
³ WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

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 six base pairs rather than the usual four (for tricyclic distamycin-like compounds). Since then, using DNA footprinting, NMR spectroscopy, isothermal titration calorimetry, and molecular dynamics, we have established that the flanking bases around the central four 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.

Keywords: DNA footprinting; DNA minor groove; Ligand affinity; NMR spectroscopy; isothermal titration calorimetry; minor groove binders; molecular dynamics.