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

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 O-6-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 O-6-guanine and O-4-thymine via B ring hydroxyl group (bond lengths lower than 2.5 angstrom). 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. (C) 2013 Elsevier Inc. All rights reserved.