Computational Analysis of Triazole-Based Kojic Acid Analogs as Tyrosinase Inhibitors by Molecular Dynamics and Free Energy Calculations

Abstract

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.

Unlocking Tyrosinase Inhibition: Insights from Molecular Dynamics and Binding Free Energy Studies of Novel Arylpiperidine and Arylpiperazine-Based Inhibitors

“…The crystal structures of TYR from Bacillus megaterium (TYRBm) were obtained from the Protein Data Bank (PDB codes 5OAE and 6EI4) as well as the arylpiperidine and arylpiperazine-based compounds (Tables 1 and 2) [19]. Molecular docking calculations were conducted using Molegro Virtual Docker (MVD) version 5.5 [28], a tool that has proven effective in TYR systems [23][24][25][26][27]. Specifically, for the docking procedures, Cu 2+ ions were represented as van der Waals spheres positioned within the catalytic site of TYR.…”

“…Specifically, for the docking procedures, Cu 2+ ions were represented as van der Waals spheres positioned within the catalytic site of TYR. Our research group has successfully utilized the MVD program to elucidate the binding modes of TYR inhibitors in previous studies [23][24][25][26][27]. Consequently, the same computational procedures were applied to the selected TYR systems.…”

“…Details regarding MD equilibration and production procedures for both the enzyme-bound and solvent-exposed (water) states can be found in our prior studies [26,27], which utilized the Q6 program [39]. Each equilibrated system underwent a total of 10 ns of MD simulations, conducted in five randomized replicas, each lasting 2 ns.…”

“…It is worth emphasizing that our molecular docking outcomes, employing the MVD package in conjunction with the MOLDOCK method [28], have demonstrated their efficacy in the context of TYR systems [23][24][25][26][27]. The MOLDOCK scoring function for each TYR inhibitor based on arylpiperidine and arylpiperazine moieties has been extracted and subsequently compared with experimental binding data (Table 3).…”

“…Our investigation sheds light on the mechanism of TYR inhibition by furnishing structural and energetic insights that align with experimental findings. Furthermore, it is important to note that all computational methodologies employed in this study have undergone rigorous validation by our research group [23][24][25][26][27].…”