Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors

Nai-Wan Hsiao, Tien-Sheng Tseng, Yu-Ching Lee, Wang-Chuan Chen, Hui-Hsiung Lin, Yun-Ru Chen, Yeng-Tseng Wang, Hung-Ju Hsu, Keng-Chang Tsai

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

Abstract

Tyrosinase, which is the crucial copper-containing enzyme involved in melanin synthesis, is strongly associated with hyperpigmentation disorders, cancer, and neurodegenerative disease; thus, it has attracted considerable interest in the fields of medicine and cosmetics. The known tyrosinase inhibitors show numerous adverse side effects, and there is a lack of safety regulations governing their use. As a result, there is a need to develop novel inhibitors with no toxicity and long-term stability. In this study, we use molecular docking and pharmacophore modeling to construct a reasonable and reliable pharmacophore model, called Hypo 1, that could be used for identifying potent natural products with crucial complementary functional groups for mushroom tyrosinase inhibition. It was observed that, out of 47 263 natural compounds, A5 structurally resembles a dipeptide (WY) and natural compound B16 is the equivalent of a tripeptide (KFY), revealing that the C-terminus tyrosine residues play a key role in tyrosinase inhibition. Tripeptides RCY and CRY, which show high tyrosinase inhibitory potency, revealed a positional and functional preference for the cysteine residue at the N-terminus of the tripeptides, essentially determining the capacity of tyrosinase inhibition. CRY and RCY used the thiol group of cysteine residues to coordinate with the Cu ions in the active site of tyrosinase and showed reduced tyrosinase activity. We discovered the novel tripeptide CRY that shows the most striking inhibitory potency against mushroom tyrosinase (IC50 = 6.16 μM); this tripeptide is more potent than the known oligopeptides and comparable with kojic acid-tripeptides. Our study provides an insight into the structural and functional roles of key amino acids of tripeptides derived from the natural compound B16, and the results are expected to be useful for the development of tyrosinase inhibitors. (Chemical Equation Presented). © 2014 American Chemical Society.
Original languageEnglish
Pages (from-to)3099-3111
Number of pages13
JournalJournal of Chemical Information and Modeling
Volume54
Issue number11
DOIs
Publication statusPublished - 2014

Keywords

  • Amino acids
  • Functional groups
  • Heavy ions
  • Neurodegenerative diseases
  • Peptides
  • Pharmacodynamics
  • Adverse side effects
  • Chemical equations
  • Long term stability
  • Mushroom tyrosinase
  • Pharmacophore modeling
  • Serendipitous discovery
  • Tyrosinase inhibition
  • Tyrosinase inhibitors
  • Plants (botany)
  • biological product
  • enzyme inhibitor
  • ligand
  • monophenol monooxygenase
  • oligopeptide
  • antagonists and inhibitors
  • chemistry
  • drug development
  • metabolism
  • molecular docking
  • protein conformation
  • sequence alignment
  • Biological Products
  • Drug Discovery
  • Enzyme Inhibitors
  • Ligands
  • Molecular Docking Simulation
  • Monophenol Monooxygenase
  • Oligopeptides
  • Protein Conformation
  • Sequence Alignment

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