Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents
Abstract
:1. Introduction
2. Results
2.1. Binding Sites
2.2. Molecular Docking on Z Site
2.3. Molecular Docking on Mepacrine Site
2.4. Molecular Docking on the Catalytic Site
2.5. Molecular Dynamic Analysis
2.5.1. Root Mean Square Deviation (RMSD) Analysis
2.5.2. Root Mean Square Fluctuation (RMSF) Analysis
2.5.3. Radius of Gyration Analysis
2.6. In Vitro Activity on Blood Trypomastigotes
2.7. Short-Term In Vivo Assay in a Murine Model of T. cruzi Infection
3. Discussion
3.1. Molecular Docking on Z Site
3.2. Molecular Docking on Mepacrine Site
3.3. Molecular Docking on the Catalytic Site
3.4. Molecular Dynamic Analysis
3.5. In Vitro Activity on Blood Trypomastigotes
3.6. Short-Term In Vivo Assay in a Murine Model of T. cruzi Infection
4. Materials and Methods
4.1. Protein Preparation
4.2. Ligand Library Preparation
4.3. Molecular Docking
4.4. Molecular Docking Analysis
4.5. Molecular Dynamic Analysis
4.6. In Vitro Trypanocidal Assay of Blood Trypomastigotes
4.7. Short-Term In Vivo Assay
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Z Site | Mepacrine Site | Catalytic Site | |||
---|---|---|---|---|---|
Drug | DS (kcal/mol) | Drug | DS (kcal/mol) | Drug | DS (kcal/mol) |
Digoxin | −10.148 | Dactinomycin | −11.136 | Flucytosine | −11.725 |
Anidulafungine | −9.873 | Irinotecan | −10.64 | Digitoxin | −11.012 |
Tannic acid | −9.551 | Posaconazole | −10.381 | Dactinomycin | −10.973 |
Metocurine | −9.238 | Digitoxin | −10.379 | Irinotecan | −10.489 |
Nilotinib | −9.203 | Tannic acid | −10.075 | Anidulafungin | −10.44 |
Palperidone | −9.186 | Flucytosine | −10.034 | Telmisartan | −10.334 |
Crizotinib | −9.169 | Regorafenib | −9.731 | Nilotinib | −10.264 |
Paclitaxel | −9.158 | Tetracaine | −9.58 | Regorafenib | −9.899 |
Dibucaine | −9.085 | Alendronate | −9.437 | Vilazodone | −9.849 |
Nafarelin | −9.051 | Sorafenib | −9.34 | Dutasteride | −9.832 |
Conivaptan | −9.049 | Telbivudine | −9.303 | Lanreotide | −9.802 |
Ponatinib | −9.047 | Digoxin | −9.169 | Zafirlukast | −9.777 |
Flucytosine | −9.031 | Dutasteride | −9.156 | Lapatinib | −9.77 |
Lomitapide | −8.979 | Temsirolimus | −9.082 | Sorafenib | −9.748 |
Edrophonium | −8.969 | Cetrorelix | −9.009 | Tetracaine | −9.718 |
Itraconazole | −8.945 | Lanreotide | −8.936 | Alendronate | −9.714 |
Vilazodone | −8.881 | Vilazodone | −8.817 | Ponatinib | −9.627 |
Regorafenib | −8.878 | Metocurine | −8.801 | Telbivudine | −9.569 |
Tolvaptan | −8.866 | Anidulafungine | −8.758 | Digoxin | −9.55 |
Ganirelix | −8.864 | Plerixafor | −8.717 | Dihidroergotamine | −9.536 |
ZINC12151998 | −10.3 | JWZ | −8.914 | ZINC12151998 | −10.799 |
7i | −9.838 | ||||
7e | −9.428 |
Drug | % Lysis at 12.5 µg/mL | LC50 µmol | ||
---|---|---|---|---|
NINOA | INC-5 | NINOA | INC-5 | |
Flucytosine | 13.4 ± 2.9 | 21.9 ± 1.5 | 613 ± 22 | 1272 ± 59 |
Alendronate | 28.2 ± 6 | 17.3 ± 15.3 | 174 ± 11 | 277 ± 13.3 |
Digoxin | 36.2 ± 2 | 33.6 ± 2.5 | 45 ± 2.8 | 76 ± 10 |
Dihydroergotamine | 29.4 ± 1.5 | 25 ± 7 | 28.1 ± 3.1 | 57 ± 2.6 |
Nifurtimox | 28.6 ± 4.5 | 25 ± 3.6 | 161 ± 33 | 255 ± 39 |
Benznidazole | 32.2 ± 6 | 30.3 ± 5.5 | 220 ± 40 | 337 ± 34 |
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Gómez-Escobedo, R.; Méndez-Álvarez, D.; Vázquez, C.; Saavedra, E.; Vázquez, K.; Alcántara-Farfán, V.; Cordero-Martínez, J.; Gonzalez-Gonzalez, A.; Rivera, G.; Nogueda-Torres, B. Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents. Molecules 2024, 29, 3796. https://doi.org/10.3390/molecules29163796
Gómez-Escobedo R, Méndez-Álvarez D, Vázquez C, Saavedra E, Vázquez K, Alcántara-Farfán V, Cordero-Martínez J, Gonzalez-Gonzalez A, Rivera G, Nogueda-Torres B. Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents. Molecules. 2024; 29(16):3796. https://doi.org/10.3390/molecules29163796
Chicago/Turabian StyleGómez-Escobedo, Rogelio, Domingo Méndez-Álvarez, Citlali Vázquez, Emma Saavedra, Karina Vázquez, Verónica Alcántara-Farfán, Joaquín Cordero-Martínez, Alonzo Gonzalez-Gonzalez, Gildardo Rivera, and Benjamín Nogueda-Torres. 2024. "Molecular Docking-Based Virtual Screening of FDA-Approved Drugs Using Trypanothione Reductase Identified New Trypanocidal Agents" Molecules 29, no. 16: 3796. https://doi.org/10.3390/molecules29163796