Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii
Abstract Toxoplasma gondii (T. gondii) is one of the most successful parasites in the world, because about a third of the world's population is seropositive for toxoplasmosis. Treatment regimens for toxoplasmosis have remained unchanged for the past 20 years, and no new drugs have been introduc...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-32388-9 |
| _version_ | 1797850098680463360 |
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| author | Zahra Gharibi Behzad Shahbazi Hamed Gouklani Hoda Nassira Zahra Rezaei Khadijeh Ahmadi |
| author_facet | Zahra Gharibi Behzad Shahbazi Hamed Gouklani Hoda Nassira Zahra Rezaei Khadijeh Ahmadi |
| author_sort | Zahra Gharibi |
| collection | DOAJ |
| description | Abstract Toxoplasma gondii (T. gondii) is one of the most successful parasites in the world, because about a third of the world's population is seropositive for toxoplasmosis. Treatment regimens for toxoplasmosis have remained unchanged for the past 20 years, and no new drugs have been introduced to the market recently. This study, performed molecular docking to identify interactions of FDA-approved drugs with essential residues in the active site of proteins of T. gondii Dihydrofolate Reductase (TgDHFR), Prolyl-tRNA Synthetase (TgPRS), and Calcium-Dependent Protein Kinase 1 (TgCDPK1). Each protein was docked with 2100 FDA-approved drugs using AutoDock Vina. Also, the Pharmit software was used to generate pharmacophore models based on the TgDHFR complexed with TRC-2533, TgPRS in complex with halofuginone, and TgCDPK1 in complex with a bumped kinase inhibitor, RM-1–132. Molecular dynamics (MD) simulation was also performed for 100 ns to verify the stability of interaction in drug–protein complexes. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis evaluated the binding energy of selected complexes. Ezetimibe, Raloxifene, Sulfasalazine, Triamterene, and Zafirlukast drugs against the TgDHFR protein, Cromolyn, Cefexim, and Lactulose drugs against the TgPRS protein, and Pentaprazole, Betamethasone, and Bromocriptine drugs against TgCDPK1 protein showed the best results. These drugs had the lowest energy-based docking scores and also stable interactions based on MD analyses with TgDHFR, TgPRS, and TgCDPK1 drug targets that can be introduced as possible drugs for laboratory investigations to treat T. gondii parasite infection. |
| first_indexed | 2024-04-09T18:54:51Z |
| format | Article |
| id | doaj.art-5cae1a5ca7fa4c22b70b7f63eaf799b2 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T18:54:51Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5cae1a5ca7fa4c22b70b7f63eaf799b22023-04-09T11:13:43ZengNature PortfolioScientific Reports2045-23222023-04-0113111810.1038/s41598-023-32388-9Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondiiZahra Gharibi0Behzad Shahbazi1Hamed Gouklani2Hoda Nassira3Zahra Rezaei4Khadijeh Ahmadi5Infectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical SciencesMolecular Medicine Department, Biotechnology Research Center, Pasteur Institute of IranInfectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical SciencesPolymer Division, Department of Chemistry, Faculty of Science, University of ZanjanProfessor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical SciencesInfectious and Tropical Diseases Research Center, Hormozgan Health Institute, Hormozgan University of Medical SciencesAbstract Toxoplasma gondii (T. gondii) is one of the most successful parasites in the world, because about a third of the world's population is seropositive for toxoplasmosis. Treatment regimens for toxoplasmosis have remained unchanged for the past 20 years, and no new drugs have been introduced to the market recently. This study, performed molecular docking to identify interactions of FDA-approved drugs with essential residues in the active site of proteins of T. gondii Dihydrofolate Reductase (TgDHFR), Prolyl-tRNA Synthetase (TgPRS), and Calcium-Dependent Protein Kinase 1 (TgCDPK1). Each protein was docked with 2100 FDA-approved drugs using AutoDock Vina. Also, the Pharmit software was used to generate pharmacophore models based on the TgDHFR complexed with TRC-2533, TgPRS in complex with halofuginone, and TgCDPK1 in complex with a bumped kinase inhibitor, RM-1–132. Molecular dynamics (MD) simulation was also performed for 100 ns to verify the stability of interaction in drug–protein complexes. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis evaluated the binding energy of selected complexes. Ezetimibe, Raloxifene, Sulfasalazine, Triamterene, and Zafirlukast drugs against the TgDHFR protein, Cromolyn, Cefexim, and Lactulose drugs against the TgPRS protein, and Pentaprazole, Betamethasone, and Bromocriptine drugs against TgCDPK1 protein showed the best results. These drugs had the lowest energy-based docking scores and also stable interactions based on MD analyses with TgDHFR, TgPRS, and TgCDPK1 drug targets that can be introduced as possible drugs for laboratory investigations to treat T. gondii parasite infection.https://doi.org/10.1038/s41598-023-32388-9 |
| spellingShingle | Zahra Gharibi Behzad Shahbazi Hamed Gouklani Hoda Nassira Zahra Rezaei Khadijeh Ahmadi Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii Scientific Reports |
| title | Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii |
| title_full | Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii |
| title_fullStr | Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii |
| title_full_unstemmed | Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii |
| title_short | Computational screening of FDA-approved drugs to identify potential TgDHFR, TgPRS, and TgCDPK1 proteins inhibitors against Toxoplasma gondii |
| title_sort | computational screening of fda approved drugs to identify potential tgdhfr tgprs and tgcdpk1 proteins inhibitors against toxoplasma gondii |
| url | https://doi.org/10.1038/s41598-023-32388-9 |
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