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.
The envelope (E) protein is an important target for antibodies in flavivirus. Literature reports that the mutation T198F, located at the domain I-II hinge of the E protein, regulates viral breathing and increases the accessibility of a distal cryptic epitope located on the fusion loop, having a direct impact in the neutralization of West Nile virus (WNV). Our study aimed to describe, using accelerated molecular dynamics simulations, the effects of the T198F mutation in the flexibility of the E protein of WNV and to elucidate the mechanism that regulates epitope accessibility. The simulation results revealed that the mutation favors the formation of alternative hydrogen bonds, hampering the bending movement between domains I and II. We hypothesized that this is the mechanism by which the T198F mutation, located at the middle of the protein, locks the distal cryptc epitope near a single preferred conformation, rendering it more prone to recognition by antibodies.
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