Docking Studies of Some Novel Kojic acid Derivatives as Possible Tyrosinase Inhibitors

Asadzadeh, Azizeh; Fassihi, Afshin; Yaghmaei, Parichehreh; Pourfarzam, Morteza

doi:10.13005/bpj/796

Cited by 17 publications

(12 citation statements)

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“…On the other hand, the oxygen present in the ortho (D5), meta (D6), and para (D2 e D4) positions in the benzene ring reduced the repulsion with the residue Phe197, thus reducing the binding free energy. Interestingly, the residues Arg191, His60, Val218, Phe197, and Glu195 showed the highest energetic contributions, which corroborates with previous results that analyzed the tyrosinase inhibition [ 17 , 18 , 19 ].…”

Section: Resultssupporting

confidence: 90%

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Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

et al. 2021

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Tyrosinases belong to the functional copper-containing proteins family, and their structure contains two copper atoms, in the active site, which are coordinated by three histidine residues. The biosynthesis of melanin in melanocytes has two stages depending on the actions of the natural substrates L-DOPA and L-tyrosine. The dysregulation of tyrosinase is involved in skin cancer initiation. In the present study, using molecular modeling tools, we analyzed the inhibition activity of tyrosinase activity using kojic acid (KA) derivatives designed from aromatic aldehydes and malononitrile. All derivatives showed conformational affinity to the enzyme active site, and a favorable distance to chelate the copper ion, which is essential for enzyme function. Molecular dynamics simulations revealed that the derivatives formed promising complexes, presenting stable conformations with deviations between 0.2 and 0.35 Å. In addition, the investigated KA derivatives showed favorable binding free energies. The most stable KA derivatives showed the following binding free energies: −17.65 kcal mol−1 (D6), −18.07 kcal mol−1 (D2), −18.13 (D5) kcal mol−1, and −10.31 kcal mol−1 (D4). Our results suggest that these derivatives could be potent competitive inhibitors of the natural substrates of L-DOPA (−12.84 kcal mol−1) and L-tyrosine (−9.04 kcal mol−1) in melanogenesis.

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Section: Resultssupporting

confidence: 90%

“…Kojic acid (KA) is a natural compound widely studied as a competitive inhibitor of tyrosinase [ 18 , 19 ]. KA prevents the formation of melanin in human melanocytes due to the reversible inhibition of tyrosinase, but it has some side effects, such as skin irritability and instability [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

et al. 2021

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“…Asn205 was suggested to be crucial for tyrosinase activity through the activation of a conserved water molecule 35 46 . The interaction of Asn205 with HQ might prevent this activation, and thus inhibit tyrosinase activity 18 47 48 . Furthermore, in the structures of TyrBm with KA at the entrance of the active site this interaction was also found to be important for KA stabilization 22 .…”

Section: Discussionmentioning

confidence: 99%

The unravelling of the complex pattern of tyrosinase inhibition

Deri

Kanteev

Goldfeder

et al. 2016

Sci Rep

132

109

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Tyrosinases are responsible for melanin formation in all life domains. Tyrosinase inhibitors are used for the prevention of severe skin diseases, in skin-whitening creams and to avoid fruit browning, however continued use of many such inhibitors is considered unsafe. In this study we provide conclusive evidence of the inhibition mechanism of two well studied tyrosinase inhibitors, KA (kojic acid) and HQ (hydroquinone), which are extensively used in hyperpigmentation treatment. KA is reported in the literature with contradicting inhibition mechanisms, while HQ is described as both a tyrosinase inhibitor and a substrate. By visualization of KA and HQ in the active site of TyrBm crystals, together with molecular modeling, binding constant analysis and kinetic experiments, we have elucidated their mechanisms of inhibition, which was ambiguous for both inhibitors. We confirm that while KA acts as a mixed inhibitor, HQ can act both as a TyrBm substrate and as an inhibitor.

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“…16 Despite extensive efforts to design and synthesize TI's, such compounds are scant and only few (e.g., PTU, anthracene, tropolone, and arbutin) have been employed in cosmetics and as therapeutic agents. [17][18][19][20][21] However, because of poor safety proles, adverse effects, or low efficacy, only a handful of them have been continued and put into practice. [22][23][24][25][26][27][28][29] Undoubtedly, now more than ever, there is an urgent need to identify and develop more efficient and safer tyrosinase inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Natural and synthetic flavonoid derivatives as new potential tyrosinase inhibitors: a systematic review

et al. 2021

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Docking Studies of Some Novel Kojic acid Derivatives as Possible Tyrosinase Inhibitors

Cited by 17 publications

References 0 publications

Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

Analysis of Kojic Acid Derivatives as Competitive Inhibitors of Tyrosinase: A Molecular Modeling Approach

The unravelling of the complex pattern of tyrosinase inhibition

Natural and synthetic flavonoid derivatives as new potential tyrosinase inhibitors: a systematic review

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