Computational Inhibition Studies of the Human Proteasome by Apigenin-7-methyl ether and its Triazole Analogues with Subunit Specificity to the β1, β2 and β5 Catalytic Sites

Abstract

Flavonoids are a multi-functional compound that possess characteristics that can be developed for therapeutic agents targeting several chronic diseases. In this computational study we have studied the binding of one flavonoid, apigenin and its triazole derivatives to the human proteasome β1, β2 and β5 catalytic sites. The computational procedure followed could be used as a platform for designing new subunit-specific inhibitors of the proteasome. The triazole analogues of apigenin have shown better binding than apigenin using the molecular docking technique. Τhe average binding energies obtained from 3 docking simulations suggest that apigenin has a binding energy of 8.89 kcal/mol, 7.79 kcal/mol and 7.59 kcal/mol for the β1, β2 and β5 catalytic sites, respectively. We found that a synthetically accessible analogue of apigenin, analogue 3c has an improved binding energy of -9.98 kcal/mol and of -10.28 kcal/mol to β1 and β5, respectively. Notable is that apigenin analogue 3a had an improved binding energy of -10.59 kcal/mol for β2 and the highest specificity for this catalytic site compared to the remaining sites. This shows that the substituted triazole moieties have significantly improved binding energies and specificities for the proteasome catalytic sites, which explains their recently found anti-cancer properties [1].