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
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...
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2024-12-01
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| Series: | Biomolecules |
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| author | César Sánchez-Juárez Roberto Flores-López Lluvia de Carolina Sánchez-Pérez Ponciano García-Gutiérrez Lucía Jiménez Abraham Landa Rafael A. Zubillaga |
| author_facet | César Sánchez-Juárez Roberto Flores-López Lluvia de Carolina Sánchez-Pérez Ponciano García-Gutiérrez Lucía Jiménez Abraham Landa Rafael A. Zubillaga |
| author_sort | César Sánchez-Juárez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6e512bf7febe4bea8be5e0e143b56b3b |
| institution | Kabale University |
| issn | 2218-273X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomolecules |
| spelling | doaj-art-6e512bf7febe4bea8be5e0e143b56b3b2025-01-24T13:24:50ZengMDPI AGBiomolecules2218-273X2024-12-01151710.3390/biom15010007Discovery 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 ToolsCésar Sánchez-Juárez0Roberto Flores-López1Lluvia de Carolina Sánchez-Pérez2Ponciano García-Gutiérrez3Lucía Jiménez4Abraham Landa5Rafael A. Zubillaga6Departmento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City C.P. 09310, MexicoDepartamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City C.P. 04510, MexicoDepartmento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City C.P. 09310, MexicoDepartmento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City C.P. 09310, MexicoDepartamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City C.P. 04510, MexicoDepartamento de Microbiología y Parasitología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City C.P. 04510, MexicoDepartmento de Química, Universidad Autónoma Metropolitana-Iztapalapa, Mexico City C.P. 09310, MexicoGlutathione 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.https://www.mdpi.com/2218-273X/15/1/7glutathione S-transferaseselective inhibitorsmolecular modeling |
| spellingShingle | César Sánchez-Juárez Roberto Flores-López Lluvia de Carolina Sánchez-Pérez Ponciano García-Gutiérrez Lucía Jiménez Abraham Landa Rafael A. Zubillaga 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 Biomolecules glutathione S-transferase selective inhibitors molecular modeling |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | glutathione S-transferase selective inhibitors molecular modeling |
| url | https://www.mdpi.com/2218-273X/15/1/7 |
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