Ab Initio Modeling and Garcinia Biflavonoids-Binding Study of Tyrosinase: The Signature Enzyme of Melanogenesis

Hyperpigmentation in humans can result from sun damage, inflammation, or other skin injuries. Tyrosinase, a crucial enzyme which catalyzes the main and rate limiting steps in melanogenesis, is a validated target in the treatment of skin hyperpigmentary disorders. Previously, employing in vitro analysis, inhibitory activities of Garcinia biflavonoid complex (kolaviron) and morelloflavone (a Garcina dulcis biflavonoid) on tyrosinase were observed. In the current study, ab initio modeling was carried out for tyrosinase and the resultant structure was employed in molecular docking to investigate the precise interaction pattern of these biflavonoids on the protein’s putative binding site. The results obtained revealed that the biflavonoids occupied the binding pocket (tropolone binding site) with one of its monoflavonoid subunits and completely barricaded the entrance of the active site with the other subunit. In this way, the biflavonoids could successfully prevent L-tyrosine and DOPA (substrates) access into the active site. Also, the biflavonoids subunit interferes with one of the two copper ions found within the binding site, an indication of their moderate inhibitory activity. Among the ligands studied, morelloflavone possessed the highest affinity (-8.5 kcal/mol) while GB1 displayed the lowest affinity (-7.6 kcal/mol) to the enzyme. Kolaflavanone and GB2 also showed modest affinity and good interaction pattern with the enzyme. These binding energy values further validate the moderate inhibitory potential of the ligands against the protein. Interestingly, these data are consistent with previous in vitro reports and thus, verify that the Garcinia biflavonoids are unique naturally-occurring competitive inhibitors of tyrosinase. Hence, their chemical scaffolds might contribute to the design and development of new tyrosinase inhibitors for combating hyperpigmentation.