Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation
Abstract The emergence of Plasmodium falciparum resistance to artemisinin-based combination therapies necessitates the development of novel antimalarial agents. This study presents the first computational investigation of steroid-tetraoxane hybrids targeting cyclophilin, a key protein implicated in...
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Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-025-13017-z |
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| author | Dipankar Nath Abhijit Debnath Malita Sarma Rajesh Kumar Singh Dipak Chetia |
| author_facet | Dipankar Nath Abhijit Debnath Malita Sarma Rajesh Kumar Singh Dipak Chetia |
| author_sort | Dipankar Nath |
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| description | Abstract The emergence of Plasmodium falciparum resistance to artemisinin-based combination therapies necessitates the development of novel antimalarial agents. This study presents the first computational investigation of steroid-tetraoxane hybrids targeting cyclophilin, a key protein implicated in artemisinin resistance mechanisms. We designed a library of 127 steroid-1,2,4,5-tetraoxane hybrid compounds combining steroidal sapogenin (∆5,(6)-diosgenin-3-one) and gem-dihydroperoxides, and employed consensus molecular docking across eight platforms to minimize algorithm-specific biases. Compound A-CY-9C emerged as the lead candidate, exhibiting superior binding stability and a favorable free energy landscape during 500 ns molecular dynamics simulations. The dual pharmacophore mechanism—disrupting parasite cholesterol uptake via the steroid component while inducing oxidative stress through the tetraoxane moiety—offers a novel strategy to combat artemisinin resistance. This first-in-class approach to targeting cyclophilin with steroid-tetraoxane hybrids provides a promising foundation for developing next-generation antimalarials against resistant P. falciparum strains. |
| format | Article |
| id | doaj-art-11bc286369344ad8a5eafeefbea106ba |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-11bc286369344ad8a5eafeefbea106ba2025-08-24T11:23:26ZengNature PortfolioScientific Reports2045-23222025-08-0115112310.1038/s41598-025-13017-zUnlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigationDipankar Nath0Abhijit Debnath1Malita Sarma2Rajesh Kumar Singh3Dipak Chetia4Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh UniversityNoida Institute of Engineering and Technology [Pharmacy Institute]Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh UniversityDepartment of Dravyaguna, Institute of Medical Sciences, Banaras Hindu UniversityDepartment of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh UniversityAbstract The emergence of Plasmodium falciparum resistance to artemisinin-based combination therapies necessitates the development of novel antimalarial agents. This study presents the first computational investigation of steroid-tetraoxane hybrids targeting cyclophilin, a key protein implicated in artemisinin resistance mechanisms. We designed a library of 127 steroid-1,2,4,5-tetraoxane hybrid compounds combining steroidal sapogenin (∆5,(6)-diosgenin-3-one) and gem-dihydroperoxides, and employed consensus molecular docking across eight platforms to minimize algorithm-specific biases. Compound A-CY-9C emerged as the lead candidate, exhibiting superior binding stability and a favorable free energy landscape during 500 ns molecular dynamics simulations. The dual pharmacophore mechanism—disrupting parasite cholesterol uptake via the steroid component while inducing oxidative stress through the tetraoxane moiety—offers a novel strategy to combat artemisinin resistance. This first-in-class approach to targeting cyclophilin with steroid-tetraoxane hybrids provides a promising foundation for developing next-generation antimalarials against resistant P. falciparum strains.https://doi.org/10.1038/s41598-025-13017-zSteroid-tetraoxane hybridsArtemisinin resistanceCyclophilin inhibitionMolecular dockingMolecular dynamicsAntimalarial drug discovery |
| spellingShingle | Dipankar Nath Abhijit Debnath Malita Sarma Rajesh Kumar Singh Dipak Chetia Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation Scientific Reports Steroid-tetraoxane hybrids Artemisinin resistance Cyclophilin inhibition Molecular docking Molecular dynamics Antimalarial drug discovery |
| title | Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| title_full | Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| title_fullStr | Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| title_full_unstemmed | Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| title_short | Unlocking the antimalarial potential of novel steroid-tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| title_sort | unlocking the antimalarial potential of novel steroid tetraoxane hybrids through consensus molecular docking and molecular dynamics investigation |
| topic | Steroid-tetraoxane hybrids Artemisinin resistance Cyclophilin inhibition Molecular docking Molecular dynamics Antimalarial drug discovery |
| url | https://doi.org/10.1038/s41598-025-13017-z |
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