Effect of methyl substitution in a ligand on the selectivity and binding affinity for a nucleobase: A case study with isoxanthopterin and its derivatives

Burki Rajendar, Arivazhagan Rajendran, Yusuke Sato, Seiichi Nishizawa, Norio Teramae

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

Abstract

Isoxanthopterin (IX) has two edges with hydrogen bond-forming sites suitable for binding to thymine (T) and cytosine (C). The binding affinity of IX for T or C is stronger than for adenine (A) and guanine (G), whereas the base selectivity of IX for T over C (and vice versa) is moderate. In order to improve both the binding affinity and base selectivity for T over C or C over T, a methyl group is introduced respectively at the N-3 or N-8 position of IX. This leads to the known ligands 3-methyl isoxanthopterin (3-MIX) and 8-methyl isoxanthopterin (8-MIX), and the binding affinity for C or T is expected to be tuned and improved by methyl substitution. Indeed, 3-MIX selectively binds to T more strongly than IX with a binding constant of 1.5 × 106 M-1 and it loses its binding affinity for C. In contrast, 8-MIX selectively binds to C over T with a binding constant of 1.0 × 106 M-1 and the binding affinity is greatly improved compared to the parent ligand IX. The thermodynamics of the ligand-nucleotide interaction is analyzed by isothermal calorimetric titrations, and the results show that the interaction follows a 1:1 stoichiometry and is enthalpy-driven. The introduction of methyl groups at both N-3 and N-8 positions results in an increase in enthalpy of the ligand-nucleotide interaction, which leads to the improved binding affinity.

Original languageEnglish
Pages (from-to)351-359
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume17
Issue number1
DOIs
Publication statusPublished - 2009 Jan 1

Keywords

  • Abasic site
  • Effect of methyl substitution
  • Fluorescence
  • Nucleobase recognition
  • Single nucleotide polymorphisms

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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