Abstract
Tyrosinase, exquisitely catalyzes the phenolic compounds into brown or black pigment, inhibition is used as a treatment for dermatological or neurodegenerative disorders. Natural products, such as cyanidin-3-O-glucoside and (−/+)-catechin, are considered safe and non-toxic food additives in tyrosinase inhibition but their ambiguous inhibitory mechanism against tyrosinase is still elusive. Thus, we presented the mechanistic insights into tyrosinase with cyanidin-3-O-glucoside and (−/+)-catechin using computational simulations and in vitro assessment. Initial molecular docking results predicted ideal docked poses (− 9.346 to − 5.795 kcal/mol) for tyrosinase with selected flavonoids. Furthermore, 100 ns molecular dynamics simulations and post-simulation analysis of docked poses established their stability and oxidation of flavonoids as substrate by tyrosinase. Particularly, metal chelation via catechol group linked with the free 3-OH group on the unconjugated dihydropyran heterocycle chain was elucidated to contribute to tyrosinase inhibition by (−/+)-catechin against cyanidin-3-O-glucoside. Also, predicted binding free energy using molecular mechanics/generalized Born surface area for each docked pose was consistent with in vitro enzyme inhibition for both mushroom and murine tyrosinases. Conclusively, (−/+)-catechin was observed for substantial tyrosinase inhibition and advocated for further investigation for drug development against tyrosinase-associated diseases.
Highlights
Melanin synthesis is a sequence of convoluted biochemical events and involves tyrosinase family proteins such as tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-21,2
Only structural variance is produced by the change in the N-terminal region signal peptides and C-terminal tails while conserved residues in the catalytic pocket of the tyrosinase protein were observed in different s pecies[7,8]
Low (10–30%) sequence similarity has been reported between the mushroom, bacterial, and human[61] while conserved residues have been studied (HisX residues) interacting with the catalytic binuclear metal center in mushroom tyrosinase (mh-Tyr), ba-Tyr, hu-Tyr, and plant tyrosinase[62]
Summary
Melanin synthesis is a sequence of convoluted biochemical events and involves tyrosinase family proteins such as tyrosinase, tyrosinase-related protein-1 (TRP-1), and TRP-21,2. Among the various natural products, ubiquitous hydroxylated flavonoids have been documented as a potent inhibitor of tyrosinase due to their structural similarities with tyrosinase substrates, such as l-tyrosine and l-DOPA, and substantial antioxidant p roperties[11,29–31]. It is apparent that polyphenolic compounds, such as flavonoids, interfere with the absorb light in spectroscopic methods to produce pseudo-mh-Tyr inhibition results[29]. Among several natural products, cyanidin-3-O-glucoside and catechins were studied and reported as mh-Tyr inhibitors using spectroscopic methods, recently reviewed elsewhere[35]. Based on these observations, it is essential to elucidate the subtle mechanistic interactions between the tyrosinase and flavonoids to provide direct evidence of the later inhibition, which is still unresolved.
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