Tyrosinase (TYR) is a metalloenzyme classified as a type-3 copper protein, which is involved in the synthesis of melanin through a catalytic process beginning with the conversion of the amino acid l-Tyrosine (l-Tyr) to l-3,4-dihydroxyphenylalanine (l-DOPA). It plays an important role in the mechanism of melanogenesis in various organisms including mammals, plants, and fungi. Herein, we used a combination of computational molecular modeling techniques including molecular dynamic (MD) simulations and the linear interaction energy (LIE) model to evaluate the binding free energy of a set of analogs of kojic acid (KA) in complex with TYR. For the MD simulations, we used a dummy model including the description of the Jahn–Teller effect for Cu2+ ions in the active site of this enzyme. Our results show that the LIE model predicts the TYR binding affinities of the inhibitor in close agreement to experimental results. Overall, we demonstrate that the classical model provides a suitable description of the main interactions between analogs of KA and Cu2+ ions in the active site of TYR.

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A carência de métodos para auxiliar o ensino de Química torna o assunto desafiador diante das didáticas de ensino. No entanto, pesquisas têm sido feitas para propor novas metodologias que visam contribuir neste sentido. Dentre as propostas, o uso do computador no auxílio ao aprendizado se destaca como sendo uma das mais promissoras. Essa metodologia pode ser bem-vinda no tratamento didático da entalpia, pois, entender esse significado requer conhecer o problema que lhe deu origem e o encaminhamento da sua solução. Neste sentido, foram realizadas simulações em um software de análise química teórica, a fim de obter a entalpia de algumas reações e compará-las com as suas entalpias experimentais. Além disso, fezse a aplicação desse método junto a graduandos em química para verificar a viabilidade em aplicar esta atividade. Assim, este trabalho apresenta a Química computacional através de métodos quânticos semiempíricos como complemento ao ensino de entalpia das reações Químicas na graduação. Palavras-chave: Química computacional, Entalpia, Ensino de QuímicaThe lack of methods to assist the chemical teaching makes the challenging issue facing the teaching didactics. However, research has been done to propose new methodologies that aim to contribute to this. Among the proposals, the use of computers to aid the learning stands out as one of the most promising. This methodology may be useful in the didactic treatment of enthalpy therefore understand this significance requires knowing the problem that gave rise to and its solutions, as well. In this sense, simulations were performed on a theoretical chemical analysis software in order to obtain the enthalpy of some reactions and comparing them with their experimental enthalpy. Besides that, application of this method with chemistry students has been employed in order to verify the viability of this activity. Thus, this work presents the computational chemistry using quantum semiempirical methods as a complement to the enthalpy of teaching of chemical reactions for undergraduate students.

Molecular docking, molecular dynamics (MD) simulations and the linear interaction energy (LIE) method were used here to predict binding modes and free energy for a set of 1,2,3-triazole-based KA analogs as potent inhibitors of Tyrosinase (TYR), a key metalloenzyme of the melanogenesis process. Initially, molecular docking calculations satisfactorily predicted the binding mode of evaluated KA analogs, where the KA part overlays the crystal conformation of the KA inhibitor into the catalytic site of TYR. The MD simulations were followed by the LIE method, which reproduced the experimental binding free energies for KA analogs with an r2 equal to 0.97, suggesting the robustness of our theoretical model. Moreover, the van der Waals contributions performed by some residues such as Phe197, Pro201, Arg209, Met215 and Val218 are responsible for the binding recognition of 1,2,3-triazole-based KA analogs in TYR catalytic site. Finally, our calculations provide suitable validation of the combination of molecular docking, MD, and LIE approaches as a powerful tool in the structure-based drug design of new and potent TYR inhibitors.

Free energy calculations explain the selectivity of peptidomimetic inhibitors to PlmIV and CatD enzymes. Insights for the development of novel potent and selective PlmIV inhibitors are provided.