Mechanism of Thymidylate Synthase Inhibition by N4-Hydroxy-(N4-Hydroxy-5-Fluoro)-dCMP in View of the Structure and Conformation of N4-Hydroxy-(N4Hydroxy-5-Fluoro)-Cytosine Calculated by the Ab Initio Quantum Mechanical Methods
Thymidylate synthase (EC 220.127.116.11) slow-binding inhibition by N4-hydroxy-dCMP (oh4dCMP) was shown to depend on conformation of the exocyclic N4-OH group, with the anti rotamer, relative to the ring N(3), indicated as an active species. 1 Potentiation of inhibition by the 5-fluoro substituent, observed for N4-hydroxy-5-fluoro-dCMP (oh4f5CMP), was explained in terms of hydrogen bonding between the N4-OH and C(5)-F groups, influencing an assumed syn-anti equilibrium by stabilization of the anti rotamer.1 In order to test the latter hypothesis two cytosine analogues, N4-hydroxy-cytosine (oh4C) and N4-hydroxy-5-fluorocytosine (oh4f5C), were theoretically studied, and their molecular structures determined, by ab initio quantum mechanical methods.
KeywordsTautomeric Form Self Consistent Field Transition State Structure Bond Saturation Self Consistent Field Method
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