Luteolin-7-O-glucoside and kaempferol 3-O-glucoside are candidate inhibitors of the Apis mellifera DNMT3 protein

Honeybees use royal jelly-controlled DNMT3-mediated epigenetic mechanisms to produce two distinct female castes, a long-lived fertile queen and a short-lived sterile worker. DNMT3 inhibition in larvae mimics the effect of royal jelly in terms of phenotypic changes that occur in adult female bees. A key question to be addressed in the honeybee genome is to identify epigenetically active compounds in royal jelly that inhibit DNMT3 and thereby determine developmental fate. Molecular docking, MMGBSA analysis, and MD simulation were performed to identify the lead candidate polyphenolic compounds from royal jelly that inhibit DNMT3. Thirteen polyphenolic compounds were docked to DNMT3 and two basic metrics, XP GScore and MMGBSA dG Bind, were used to evaluate the binding affinity. The highest binding affinity was observed for luteolin 7-O-glucoside with a docking score of −10.3 and kaempferol 3-O-glucoside with −8.9. Furthermore, the two compounds exhibited high total binding energies of −52.8 and −64.85 kJ/mol, respectively. MD simulations show that, unlike kaempferol 3-O-glucoside, luteolin-7-O-glucoside maintains a consistent interaction with the DNMT3 throughout the simulation period. These results suggest that of the 13 polyphenolic compounds in royal jelly, luteolin-7-O-glucoside is the most promising candidate to be the component responsible for most of the DNMT3 inhibitory activity in this diet.