Application of two-layer ONIOM for studying the interaction of N-substituted piperazinylfluoroquinolones with ds-DNA

作者：Ahmadi F^*; Jahangard Yekta S; Heidari Moghadam A; Aliabadi A R

来源：Computational and Theoretical Chemistry, 2013, 1006: 9-18.

DOI：10.1016/j.comptc.2012.11.006

• N-substituted piperazinylfluoroquinolones
• Two layers ONIOM
• DFT MPWB1K
• DNA(AT-AT)2
• DNA(CG-CG)2

The pharmacological in vitro tests of four N-substituted piperazinylfluoroquinolones (N4-P-CIPRO, N4-P-ENOX, N4-P-Nor and N4-P-Nor-Ph) pointed out that these compounds have a significant cytotoxicity activity on human ovarian carcinoma comparable to that of ciprofloxacin, norfloxacin, enoxacin and etoposide as control tests, hypothesizing that this in vitro cytotoxic activity might be due to the interaction with DNA. To evaluate this hypothesis, we used two-layered ONIOM method (DFT MPWB1K 6-31+G(d):UFF) for studying the interaction of these N-substituted piperazinyl-fluoroquinolones compounds with modeled DNA(AT-AT)2 and DNA(CG-CG)2 in gas and aqueous phases. The calculated values of the interaction energy of these compounds with DNA(AT-AT)2 and DNA(CG-CG)2 as well as with AT and CG base pairs, supported a static higher affinity toward AT compared to CG DNA base sequences. Furthermore, the results revealed that the affinity of these compounds to DNA(AT-AT)2 base pairs is as follows: N4-P-NOR-Ph > N4-P-CIPRO > N4-P-NOR > N4-P-ENOX; and for DNA(CG-CG)2 base pair: N4-P-NOR-Ph > N4-P-CIPRO > N4-P-NOR > N4-P-ENOX. We concluded that, these compounds may have one possible mode of non-covalent binding of ligands to DNA, namely minor groove binding. However, our results are in agreement with the experimentally in vitro cytotoxicity test.

• 出版日期2013-2-15