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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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-13017-z |
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| Summary: | 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. |
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| ISSN: | 2045-2322 |