Dietary flavonoid narirutin as a prospective antagonist of oncogenic pri/pre-microRNAs

MicroRNAs (miRNAs) are involved in cancer progression via translational degradation in a sequence-specific manner of the 3'-untranslated region (3'UTR) of messenger RNA (mRNA). The involvement of miRNA in the biological progression of various cancer types is considered to be a potential target. Primary miRNA (pri-miRNA) and precursor-miRNA (pre-miRNA) synthesize the miRNA by dicer-catalyzed processes thus targeting pri/pre-miRNA by phytochemicals is amongst the appropriate approaches for anticancer therapies. Flavonoids category of phytochemicals is well-known for its chemotherapeutic and chemopreventive potential against multiple cancer types. However, the molecular interactions of flavonoids with miRNAs are not reported so far. Thus, this study aims to identify the promising flavonoids as the antagonist of miRNAs (pre-miR21, pri-miR-208a, pri-miR-378a, pri-miR320b, pri-miR-300, pri-miR-19b, and pre-miR-20b) using molecular docking simulations studies. Among the tested flavonoids, narirutin showed highest binding energy (-11.7 kcal/mol) against pri-miR19b followed by pri-miR-378a (-11.4 kcal/mol) >  pri-miR320b (-11.2 kcal/mol) =  pri-miR-300 (-11.2 kcal/mol) >  pri-miR-208a (-9.0 kcal/mol) >  pre-miR-20b (- 8.3 kcal/mol). The molecular dynamic simulation experiment confirmed that narirutin destabilizes the tertiary structure of pri-miRNA in comparison to apo-RNA. The finding indicates that narirutin binding with pre-miRNA causes disruption of pri-RNA structure that creates a loss of DICER-pre-miRNA interactions by hindering the pre-miRNA synthesis, thereby affecting miRNA processing. Further pharmacokinetics and toxicity prediction revealed that it is non-carcinogenic, non-mutagenic, and does not inhibit the CYPs activity. Thus, narirutin could be a possible antagonist of oncogenic miRNAs, therefore could be useful for miRNA-targeted cancer prevention and treatment.