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 journalArticle

17 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

Fingerprint

Neurodegenerative diseases
Melanin
Monophenol Monooxygenase
Cosmetics
Biological Products
Functional groups
Peptides
Medicine
Toxicity
Amino acids
Enzymes
Copper
cosmetics
Acids
Ions
cancer
Group
medicine
Disease
regulation

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

Cite this

Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors. / Hsiao, Nai-Wan; Tseng, Tien-Sheng; Lee, Yu-Ching; Chen, Wang-Chuan; Lin, Hui-Hsiung; Chen, Yun-Ru; Wang, Yeng-Tseng; Hsu, Hung-Ju; Tsai, Keng-Chang.

In: Journal of Chemical Information and Modeling, Vol. 54, No. 11, 2014, p. 3099-3111.

Research output: Contribution to journalArticle

Hsiao, N-W, Tseng, T-S, Lee, Y-C, Chen, W-C, Lin, H-H, Chen, Y-R, Wang, Y-T, Hsu, H-J & Tsai, K-C 2014, 'Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors', Journal of Chemical Information and Modeling, vol. 54, no. 11, pp. 3099-3111. https://doi.org/10.1021/ci500370x
Hsiao, Nai-Wan ; Tseng, Tien-Sheng ; Lee, Yu-Ching ; Chen, Wang-Chuan ; Lin, Hui-Hsiung ; Chen, Yun-Ru ; Wang, Yeng-Tseng ; Hsu, Hung-Ju ; Tsai, Keng-Chang. / Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors. In: Journal of Chemical Information and Modeling. 2014 ; Vol. 54, No. 11. pp. 3099-3111.
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title = "Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors",
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). {\circledC} 2014 American Chemical Society.",
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",
author = "Nai-Wan Hsiao and Tien-Sheng Tseng and Yu-Ching Lee and Wang-Chuan Chen and Hui-Hsiung Lin and Yun-Ru Chen and Yeng-Tseng Wang and Hung-Ju Hsu and Keng-Chang Tsai",
note = "被引用次數:3 Export Date: 28 March 2016 CODEN: JCISD 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, Ministry of Health and WelfareTaiwan 化學物質/CAS: monophenol monooxygenase, 9002-10-2; Biological Products; Enzyme Inhibitors; Ligands; Monophenol Monooxygenase; Oligopeptides 參考文獻: Costin, G.E., Hearing, V.J., Human skin pigmentation: Melanocytes modulate skin color in response to stress (2007) FASEB J., 21, pp. 976-994; Alexis, A., Barbosa, V.H., (2013) Skin of Color: A Practical Guide to Dermatologic Diagnosis and Treatment, , Springer: Berlin, Heidelberg; Piamphongsant, T., Treatment of melasma: A review with personal experience (1998) Int. J. Dermatol., 37, pp. 897-903; Cavalieri, E.L., Li, K.M., Balu, N., Saeed, M., Devanesan, P., Higginbotham, S., Zhao, J., Rogan, E.G., Catechol orthoquinones: The electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases (2002) Carcinogenesis, 23, pp. 1071-1077; Kim, Y.J., Uyama, H., Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future (2005) Cell. Mol. Life Sci., 62, pp. 1707-1723; Eisenhofer, G., Tian, H., Holmes, C., Matsunaga, J., Roffler-Tarlov, S., Hearing, V.J., Tyrosinase: A developmentally specific major determinant of peripheral dopamine (2003) FASEB J., 17, pp. 1248-1255; Chang, T.S., An updated review of tyrosinase inhibitors (2009) Int. J. Mol. Sci., 10, pp. 2440-2475; Slominski, A., Tobin, D.J., Shibahara, S., Wortsman, J., Melanin pigmentation in mammalian skin and its hormonal regulation (2004) Physiol. Rev., 84, pp. 1155-1228; Pan, T., Li, X., Jankovic, J., The association between Parkinson's disease and melanoma (2011) Int. J. Cancer, 128, pp. 2251-2260; Asanuma, M., Miyazaki, I., Ogawa, N., Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease (2003) Neurotox Res., 5, pp. 165-176; Seo, S.Y., Sharma, V.K., Sharma, N., Mushroom tyrosinase: Recent prospects (2003) J. Agric. Food Chem., 51, pp. 2837-2853; Elsner, P., Maibach, H.I., Cosmeceuticals: Drugs vs. Cosmetics (2000) Cosmetic Science and Technology Series, 23. , Marcel Dekker: New York; Maeda, K., Fukuda, M., Arbutin: Mechanism of its depigmenting action in human melanocyte culture (1996) J. Pharmacol. Exp. Ther., 276, pp. 765-769; Schurink, M., Van Berkel, W.J., Wichers, H.J., Boeriu, C.G., Novel peptides with tyrosinase inhibitory activity (2007) Peptides, 28, pp. 485-495; Germanas, J.P., Wang, S., Miner, A., Hao, W., Ready, J.M., Discovery of small-molecule inhibitors of tyrosinase (2007) Bioorg. Med. Chem. Lett., 17, pp. 6871-6875; Smith, M.T., Yager, J.W., Steinmetz, K.L., Eastmond, D.A., Peroxidase-dependent metabolism of benzene' s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity (1989) Environ. Health Perspect., 82, pp. 23-29; Rossi, L., Moore, G.A., Orrenius, S., O'Brien, P.J., Quinone toxicity in hepatocytes without oxidative stress (1986) Arch. Biochem. Biophys., 251, pp. 25-35; DeCaprio, A.P., The toxicology of hydroquinone - Relevance to occupational and environmental exposure (1999) Crit. Rev. Toxicol., 29, pp. 283-330; Fuyuno, I., Spotlight turns on cosmetics for Asian skin (2004) Nature, 432, p. 938; Girelli, A.M., Mattei, E., Messina, A., Tarola, A.M., Inhibition of polyphenol oxidases activity by various dipeptides (2004) J. Agric. Food Chem., 52, pp. 2741-2745; Abu Ubeid, A., Zhao, L., Wang, Y., Hantash, B.M., Short-sequence oligopeptides with inhibitory activity against mushroom and human tyrosinase (2009) J. Invest. Dermatol., 129, pp. 2242-2249; Kim, H., Choi, J., Cho, J.K., Kim, S.Y., Lee, Y.S., Solid-phase synthesis of kojic acid -tripeptides and their tyrosinase inhibitory activity, storage stability, and toxicity (2004) Bioorg. Med. Chem. Lett., 14, pp. 2843-2846; Morita, H., K, T., Kobata, H., Gonda, A., Takeya, K., Itokawa, H., Pseudostellarins D -F, new tyrosinase inhibitory cyclic peptides from Pseudostellaria heterophylla (1994) Tetrahedron, pp. 9975-9982; Shimizu, K., Kondo, R., Sakai, K., Inhibition of tyrosinase by flavonoids, stilbenes and related 4-substituted resorcinols: Structure - Activity investigations (2000) Planta Med., 66, pp. 11-15; Zheng, Z.P., Cheng, K.W., To, J.T., Li, H., Wang, M., Isolation of tyrosinase inhibitors from Artocarpus heterophyllus and use of its extract as antibrowning agent (2008) Mol. Nutr. Food Res., 52, pp. 1530-1538; Tajima, R., Oozeki, H., Muraoka, S., Tanaka, S., Motegi, Y., Nihei, H., Yamada, Y., Nihei, K., Synthesis and evaluation of bibenzyl glycosides as potent tyrosinase inhibitors (2011) Eur. J. Med. Chem., 46, pp. 1374-1381; Bao, K., Dai, Y., Zhu, Z.B., Tu, F.J., Zhang, W.G., Yao, X.S., Design and synthesis of biphenyl derivatives as mushroom tyrosinase inhibitors (2010) Bioorg. Med. Chem., 18, pp. 6708-6714; Yi, W., Cao, R., Peng, W., Wen, H., Yan, Q., Zhou, B., Ma, L., Song, H., Synthesis and biological evaluation of novel 4-hydroxybenzaldehyde derivatives as tyrosinase inhibitors (2010) Eur. J. Med. Chem., 45, pp. 639-646; Casanola-Martin, G.M., Marrero-Ponce, Y., Tareq Hassan Khan, M., Torrens, F., Perez-Gimenez, F., Rescigno, A., Atom- and bond-based 2D TOMOCOMD-CARDD approach and ligand-based virtual screening for the drug discovery of new tyrosinase inhibitors (2008) J. Biomol. Screen., 13, pp. 1014-1024; Ryu, Y.B., Westwood, I.M., Kang, N.S., Kim, H.Y., Kim, J.H., Moon, Y.H., Park, K.H., Kurarinol, tyrosinase inhibitor isolated from the root of Sophora flavescens (2008) Phytomedicine, 15, pp. 612-618; Marrero-Ponce, Y., Khan, M.T., Casanola-Martin, G.M., Ather, A., Sultankhodzhaev, M.N., Garcia-Domenech, R., Torrens, F., Rotondo, R., Bond-based 2D TOMOCOMD-CARDD approach for drug discovery: Aiding decision-making in {"}in silico{"} selection of new lead tyrosinase inhibitors (2007) J. Comput. Aided Mol. Des., 21, pp. 167-188; Ahmad, V.U., Ullah, F., Hussain, J., Farooq, U., Zubair, M., Khan, M.T., Choudhary, M.I., Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies (2004) Chem. Pharm. Bull. 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year = "2014",
doi = "10.1021/ci500370x",
language = "English",
volume = "54",
pages = "3099--3111",
journal = "Journal of Chemical Information and Computer Sciences",
issn = "0095-2338",
publisher = "American Chemical Society",
number = "11",

}

TY - JOUR

T1 - Serendipitous discovery of short peptides from natural products as tyrosinase inhibitors

AU - Hsiao, Nai-Wan

AU - Tseng, Tien-Sheng

AU - Lee, Yu-Ching

AU - Chen, Wang-Chuan

AU - Lin, Hui-Hsiung

AU - Chen, Yun-Ru

AU - Wang, Yeng-Tseng

AU - Hsu, Hung-Ju

AU - Tsai, Keng-Chang

N1 - 被引用次數:3 Export Date: 28 March 2016 CODEN: JCISD 通訊地址: Tsai, K.-C.; National Research Institute of Chinese Medicine, Ministry of Health and WelfareTaiwan 化學物質/CAS: monophenol monooxygenase, 9002-10-2; Biological Products; Enzyme Inhibitors; Ligands; Monophenol Monooxygenase; Oligopeptides 參考文獻: Costin, G.E., Hearing, V.J., Human skin pigmentation: Melanocytes modulate skin color in response to stress (2007) FASEB J., 21, pp. 976-994; Alexis, A., Barbosa, V.H., (2013) Skin of Color: A Practical Guide to Dermatologic Diagnosis and Treatment, , Springer: Berlin, Heidelberg; Piamphongsant, T., Treatment of melasma: A review with personal experience (1998) Int. J. Dermatol., 37, pp. 897-903; Cavalieri, E.L., Li, K.M., Balu, N., Saeed, M., Devanesan, P., Higginbotham, S., Zhao, J., Rogan, E.G., Catechol orthoquinones: The electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases (2002) Carcinogenesis, 23, pp. 1071-1077; Kim, Y.J., Uyama, H., Tyrosinase inhibitors from natural and synthetic sources: Structure, inhibition mechanism and perspective for the future (2005) Cell. Mol. Life Sci., 62, pp. 1707-1723; Eisenhofer, G., Tian, H., Holmes, C., Matsunaga, J., Roffler-Tarlov, S., Hearing, V.J., Tyrosinase: A developmentally specific major determinant of peripheral dopamine (2003) FASEB J., 17, pp. 1248-1255; Chang, T.S., An updated review of tyrosinase inhibitors (2009) Int. J. Mol. Sci., 10, pp. 2440-2475; Slominski, A., Tobin, D.J., Shibahara, S., Wortsman, J., Melanin pigmentation in mammalian skin and its hormonal regulation (2004) Physiol. Rev., 84, pp. 1155-1228; Pan, T., Li, X., Jankovic, J., The association between Parkinson's disease and melanoma (2011) Int. J. Cancer, 128, pp. 2251-2260; Asanuma, M., Miyazaki, I., Ogawa, N., Dopamine- or L-DOPA-induced neurotoxicity: The role of dopamine quinone formation and tyrosinase in a model of Parkinson's disease (2003) Neurotox Res., 5, pp. 165-176; Seo, S.Y., Sharma, V.K., Sharma, N., Mushroom tyrosinase: Recent prospects (2003) J. Agric. Food Chem., 51, pp. 2837-2853; Elsner, P., Maibach, H.I., Cosmeceuticals: Drugs vs. Cosmetics (2000) Cosmetic Science and Technology Series, 23. , Marcel Dekker: New York; Maeda, K., Fukuda, M., Arbutin: Mechanism of its depigmenting action in human melanocyte culture (1996) J. Pharmacol. Exp. Ther., 276, pp. 765-769; Schurink, M., Van Berkel, W.J., Wichers, H.J., Boeriu, C.G., Novel peptides with tyrosinase inhibitory activity (2007) Peptides, 28, pp. 485-495; Germanas, J.P., Wang, S., Miner, A., Hao, W., Ready, J.M., Discovery of small-molecule inhibitors of tyrosinase (2007) Bioorg. Med. Chem. Lett., 17, pp. 6871-6875; Smith, M.T., Yager, J.W., Steinmetz, K.L., Eastmond, D.A., Peroxidase-dependent metabolism of benzene' s phenolic metabolites and its potential role in benzene toxicity and carcinogenicity (1989) Environ. Health Perspect., 82, pp. 23-29; Rossi, L., Moore, G.A., Orrenius, S., O'Brien, P.J., Quinone toxicity in hepatocytes without oxidative stress (1986) Arch. Biochem. Biophys., 251, pp. 25-35; DeCaprio, A.P., The toxicology of hydroquinone - Relevance to occupational and environmental exposure (1999) Crit. Rev. Toxicol., 29, pp. 283-330; Fuyuno, I., Spotlight turns on cosmetics for Asian skin (2004) Nature, 432, p. 938; Girelli, A.M., Mattei, E., Messina, A., Tarola, A.M., Inhibition of polyphenol oxidases activity by various dipeptides (2004) J. Agric. Food Chem., 52, pp. 2741-2745; Abu Ubeid, A., Zhao, L., Wang, Y., Hantash, B.M., Short-sequence oligopeptides with inhibitory activity against mushroom and human tyrosinase (2009) J. Invest. Dermatol., 129, pp. 2242-2249; Kim, H., Choi, J., Cho, J.K., Kim, S.Y., Lee, Y.S., Solid-phase synthesis of kojic acid -tripeptides and their tyrosinase inhibitory activity, storage stability, and toxicity (2004) Bioorg. Med. Chem. Lett., 14, pp. 2843-2846; Morita, H., K, T., Kobata, H., Gonda, A., Takeya, K., Itokawa, H., Pseudostellarins D -F, new tyrosinase inhibitory cyclic peptides from Pseudostellaria heterophylla (1994) Tetrahedron, pp. 9975-9982; Shimizu, K., Kondo, R., Sakai, K., Inhibition of tyrosinase by flavonoids, stilbenes and related 4-substituted resorcinols: Structure - Activity investigations (2000) Planta Med., 66, pp. 11-15; Zheng, Z.P., Cheng, K.W., To, J.T., Li, H., Wang, M., Isolation of tyrosinase inhibitors from Artocarpus heterophyllus and use of its extract as antibrowning agent (2008) Mol. Nutr. Food Res., 52, pp. 1530-1538; Tajima, R., Oozeki, H., Muraoka, S., Tanaka, S., Motegi, Y., Nihei, H., Yamada, Y., Nihei, K., Synthesis and evaluation of bibenzyl glycosides as potent tyrosinase inhibitors (2011) Eur. J. Med. Chem., 46, pp. 1374-1381; Bao, K., Dai, Y., Zhu, Z.B., Tu, F.J., Zhang, W.G., Yao, X.S., Design and synthesis of biphenyl derivatives as mushroom tyrosinase inhibitors (2010) Bioorg. Med. Chem., 18, pp. 6708-6714; Yi, W., Cao, R., Peng, W., Wen, H., Yan, Q., Zhou, B., Ma, L., Song, H., Synthesis and biological evaluation of novel 4-hydroxybenzaldehyde derivatives as tyrosinase inhibitors (2010) Eur. J. Med. Chem., 45, pp. 639-646; Casanola-Martin, G.M., Marrero-Ponce, Y., Tareq Hassan Khan, M., Torrens, F., Perez-Gimenez, F., Rescigno, A., Atom- and bond-based 2D TOMOCOMD-CARDD approach and ligand-based virtual screening for the drug discovery of new tyrosinase inhibitors (2008) J. Biomol. Screen., 13, pp. 1014-1024; Ryu, Y.B., Westwood, I.M., Kang, N.S., Kim, H.Y., Kim, J.H., Moon, Y.H., Park, K.H., Kurarinol, tyrosinase inhibitor isolated from the root of Sophora flavescens (2008) Phytomedicine, 15, pp. 612-618; Marrero-Ponce, Y., Khan, M.T., Casanola-Martin, G.M., Ather, A., Sultankhodzhaev, M.N., Garcia-Domenech, R., Torrens, F., Rotondo, R., Bond-based 2D TOMOCOMD-CARDD approach for drug discovery: Aiding decision-making in "in silico" selection of new lead tyrosinase inhibitors (2007) J. Comput. Aided Mol. Des., 21, pp. 167-188; Ahmad, V.U., Ullah, F., Hussain, J., Farooq, U., Zubair, M., Khan, M.T., Choudhary, M.I., Tyrosinase inhibitors from Rhododendron collettianum and their structure-activity relationship (SAR) studies (2004) Chem. Pharm. Bull. 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PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

KW - Amino acids

KW - Functional groups

KW - Heavy ions

KW - Neurodegenerative diseases

KW - Peptides

KW - Pharmacodynamics

KW - Adverse side effects

KW - Chemical equations

KW - Long term stability

KW - Mushroom tyrosinase

KW - Pharmacophore modeling

KW - Serendipitous discovery

KW - Tyrosinase inhibition

KW - Tyrosinase inhibitors

KW - Plants (botany)

KW - biological product

KW - enzyme inhibitor

KW - ligand

KW - monophenol monooxygenase

KW - oligopeptide

KW - antagonists and inhibitors

KW - chemistry

KW - drug development

KW - metabolism

KW - molecular docking

KW - protein conformation

KW - sequence alignment

KW - Biological Products

KW - Drug Discovery

KW - Enzyme Inhibitors

KW - Ligands

KW - Molecular Docking Simulation

KW - Monophenol Monooxygenase

KW - Oligopeptides

KW - Protein Conformation

KW - Sequence Alignment

U2 - 10.1021/ci500370x

DO - 10.1021/ci500370x

M3 - Article

VL - 54

SP - 3099

EP - 3111

JO - Journal of Chemical Information and Computer Sciences

JF - Journal of Chemical Information and Computer Sciences

SN - 0095-2338

IS - 11

ER -