Discovery and Characterization of Two Selective Inhibitors for a Mu-Class Glutathione S-Transferase of 25 kDa from <i>Taenia solium</i> Using Computational and Bioinformatics Tools
2024
César Sánchez-Juárez | Roberto Flores-López | Lluvia de Carolina Sánchez-Pérez | Ponciano García-Gutiérrez | Lucía Jiménez | Abraham Landa | Rafael A. Zubillaga
Glutathione S-transferases (GSTs) are promising pharmacological targets for developing antiparasitic agents against helminths, as they play a key role in detoxifying cytotoxic xenobiotics and managing oxidative stress. Inhibiting GST activity can compromise parasite viability. This study reports the successful identification of two selective inhibitors for the mu-class glutathione S-transferase of 25 kDa (Ts25GST) from <i>Taenia solium</i>, named <i>i11</i> and <i>i15</i>, using a computationally guided approach. The workflow involved modeling and refining the 3D structure from the sequence using the AlphaFold algorithm and all-atom molecular dynamics simulations with an explicit solvent. Representative structures from these simulations and a putative binding site with low conservation relative to human GSTs, identified via the SILCS methodology, were employed for virtual screening through ensemble docking against a commercial compound library. The two compounds were found to reduce the enzyme’s activity by 50–70% under assay conditions, while showing a reduction of only 30–35% for human mu-class GSTM1, demonstrating selectivity for Ts25GST. Notable, <i>i11</i> displayed competitive inhibition with CDNB, while <i>i15</i> exhibited a non-competitive inhibition type.
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