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首页> 外文期刊>Biochemical Pharmacology >Combining molecular docking and 3-D pharmacophore generation to enclose the in vivo antigenotoxic activity of naturally occurring aromatic compounds: Myricetin, quercetin, rutin, and rosmarinic acid
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Combining molecular docking and 3-D pharmacophore generation to enclose the in vivo antigenotoxic activity of naturally occurring aromatic compounds: Myricetin, quercetin, rutin, and rosmarinic acid

机译：结合分子对接和3-D药效团生成以封闭天然存在的芳族化合物（杨梅，槲皮素，芦丁和迷迭香酸）的体内抗原毒性活性

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摘要

Considering the controversial results concerning the antimutagenicity of some phenolic compounds recorded in the literature, the antigenotoxic effects of four selected phenolic compounds, myricetin, quercetin, rutin, and rosmarinic acid, against DNA damage induced by alkylation with ethyl methanesulfonate (EMS), were evaluated in Drosophila melanogaster males using the sex-linked recessive lethal (SLRL) test. To assess the protective effects against DNA damage, D. melanogaster males were exposed to a monofunctional alkylating agent EMS in concentration of 0.75 ppm, 24 h prior to one of the selected phenolic compounds in the concentration of 100 ppm. The possible differences in mechanisms of protection by selected compounds were determined by molecular docking, after which structure-based 3-D pharmacophore models were generated. EMS induced considerable DNA damage as shown by significant increase in the frequency of germinative mutations. The frequency decreased with high significance (p 0.001***) after post-treatments with all selected phenolic compounds. Further, docking analysis revealed EMS pre-bond conformations against guanine and thymine as a necessary condition for alkylation, after which resulting O6-ethylguanine and O 4-ethylthimine were docked into the active site of O 6-alkylguanine-DNA alkyltransferase to confirm that particular lesions are going to be repaired. Finally, myricetin and quercetin protected dealkylated nucleotides from further EMS alkylation by forming the strong hydrogen bonds with O6-guanine and O4-thymine via B ring hydroxyl group (bond lengths lower than 2.5 ?). On the other side, rutin and rosmarinic acid encircled nucleotides and by fulfilling the EMS binding space they made an impermeable barrier for the EMS molecule and prevented further alkylation.
机译：考虑到有关文献中记录的某些酚类化合物的抗突变性的有争议的结果，评估了四种选择的酚类化合物（杨梅素，槲皮素，芦丁和迷迭香酸）对甲磺酸乙酯（EMS）烷基化引起的DNA损伤的抗原毒性作用。果蝇雄性果蝇使用性连锁隐性致死（SLRL）测试。为了评估针对DNA损伤的保护作用，在选择的一种酚类化合物的浓度为100 ppm之前的24小时，将黑腹果蝇雄性暴露于0.75 ppm的单官能烷基化剂EMS中。通过分子对接确定所选化合物保护机制的可能差异，然后生成基于结构的3-D药效团模型。 EMS引起了可观的DNA损伤，如发芽突变频率的显着增加所显示。在用所有选定的酚类化合物进行后处理后，频率降低具有显着性（p <0.001 ***）。此外，对接分析表明，针对鸟嘌呤和胸腺嘧啶的EMS预键构象是烷基化的必要条件，此后，将所得的O6-乙基鸟嘌呤和O 4-乙基嘧啶对接至O 6-烷基鸟嘌呤-DNA烷基转移酶的活性位点，以确认特定的病变将被修复。最后，杨梅素和槲皮素通过B环羟基与O6-鸟嘌呤和O4-胸腺嘧啶形成强氢键（键长小于2.5？），从而保护脱烷基核苷酸免受进一步的EMS烷基化影响。另一方面，芦丁和迷迭香酸环绕核苷酸，通过满足EMS结合空间，它们为EMS分子形成了不可渗透的屏障，并阻止了进一步的烷基化。

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