Abstract
Halogen-modified nucleic acid molecules, such as trifluorothymidine (FTD) and 5-fluorouracil, are widely used in medical science and clinical site. These compounds have a very similar nucleobase structure. It is reported that both of these compounds could be incorporated into DNA. The incorporation of FTD produces highly anti-tumor effect. However, it is not known whether to occur a significant effect by the incorporation of 5-fluorouracil. Nobody knows why such a difference will occur. To understand the reason why there is large differences between trifluorothymidine and 5-fluorouracil, we have performed the molecular dynamics simulations and molecular orbital calculations. Although the active interaction energy between Halogen-modified nucleic acids or and complementary adenine was increased, in only FTD incorporated DNA, more strongly dispersion force interactions with an adjacent base were detected in many thermodynamic DNA conformations. As the results, the conformational changes occur even if it is in internal body temperature. Then the break of hydrogen bonding between FTD and complementary adenine base occur more frequently. The double helix structural destabilization of DNA with FTD is resulted from autoagglutination caused by the bonding via halogen orbitals such as halogen bonding and the general van der Waals interactions such as CH–{rm{pi }}, lone pair (LP)–{rm{pi }}, and {rm{pi }}–{rm{pi }} interactions. Therefore, it is strongly speculated that such structural changes caused by trifluoromethyl group is important for the anti-tumor effect of FTD alone.
Highlights
Some types of nucleic acid modifications such as methylation and acetylation are known to directly affect the functions of DNA and RNA
We constructed simple base pair models, model 1, model 2, and model 3 (Fig. 1A–C), to analyze the difference in the hydrogen bonding intensity according to the presence or absence of the fluorine substituent and dissociation energies between thymidine– adenine, deoxyribose 5FU–adenine, and fluorouracil (5FU) and trifluorothymidine (FTD)–adenine pairs, respectively
All ab initio molecular orbital calculations were performed with Gaussian 0923
Summary
It is said today that the reason is not to form a covalent bond with thymidylate synthase[17] but to lead to DNA dysfunction by the incorporation of FTD into DNA from some experimental results[18,19,20,21,22]. In this way, despite all the different pharmacological mechanisms, the structures of the base moieties of 5FU and FTD are very similar.
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