TY - JOUR
T1 - Effect of methyl substitution in a ligand on the selectivity and binding affinity for a nucleobase
T2 - A case study with isoxanthopterin and its derivatives
AU - Rajendar, Burki
AU - Rajendran, Arivazhagan
AU - Sato, Yusuke
AU - Nishizawa, Seiichi
AU - Teramae, Norio
N1 - Funding Information:
This work was partially supported by Grants-in-Aid for Scientific Research (A) (No. 17205009), for Scientific Research (B) (No. 18350039), and for the Global COE Project, Molecular Complex Chemistry, from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
PY - 2009/1/1
Y1 - 2009/1/1
N2 - 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.
AB - 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.
KW - Abasic site
KW - Effect of methyl substitution
KW - Fluorescence
KW - Nucleobase recognition
KW - Single nucleotide polymorphisms
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U2 - 10.1016/j.bmc.2008.10.062
DO - 10.1016/j.bmc.2008.10.062
M3 - Article
C2 - 19010683
AN - SCOPUS:57649176767
VL - 17
SP - 351
EP - 359
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 1
ER -