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

Abstract

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.

Synthesis of Novel Tritopic Hydrazone Ligands: Spectroscopy, Biological Activity, DFT, and Molecular Docking Studies

“…To investigate and compare the antimicrobial activity of the synthesized compounds, docking analyses of L1 and L2 against tyrosinase from Bacillus megaterium were performed. It is well-known that the tyrosinase of Bacillus megaterium bacteria is an attractive target for the development of antimicrobials or antibiotic adjuvants for the treatment of hyperpigmentation because of its similarity (33.5%) to the human enzyme [ 96 , 97 , 98 , 99 ]. The docking results were compared with well-testified inhibitor arbutin [ 97 ].…”

Antioxidant and anti‐tyrosinase activity of a novel stilbene analogue as an anti‐browning agent

“…Although KA has been used as an ingredient in cosmetics and as an anti‐browning agent in the food industry, its anti‐tyrosinase activity is relatively low. Chemical modification of KA provides a promising route to improve anti‐tyrosinase activity 12 …”

“…Chemical modification of KA provides a promising route to improve anti-tyrosinase activity. 12 Polyphenolic compounds are the largest group of phytochemicals found in plants and generally act as good tyrosinase inhibitors. 13 Among these compounds, stilbenes have received considerable interest.…”

Inhibitory Effect of Chlorogenic Acid Analogues Comprising Pyridine and Pyrimidine on α-MSH-Stimulated Melanogenesis and Stability of Acyl Analogues in Methanol

“…Several small heterocyclic molecules are playing a vital role in the field of medicinal chemistry. A wide variety of synthetic agents such as kojic acid derivatives [30][31][32], thiosemicarbazones [28,33], Morita-Baylis-Hillman adducts [34], quinazolinone benzamides [35,36], and cinnamic acid derivatives [37,38] are reported for the treatment of hyperpigmentation disorders. Pyridine is a common structural motif that is ubiquitous in several pharmaceuticals and natural products including vitamins and alkaloids [39][40][41][42].…”