Nath Dipankar, Debnath Abhijit, Sarma Malita, Singh Rajesh Kumar, Chetia Dipak
Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, 786004, Assam, India.
Noida Institute of Engineering and Technology [Pharmacy Institute], 19 Knowledge Park-II, Institutional Area, Greater Noida, Uttar Pradesh, India.
Sci Rep. 2025 Aug 19;15(1):30389. doi: 10.1038/s41598-025-13017-z.
The emergence of 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 (∆-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 strains.
The online version contains supplementary material available at 10.1038/s41598-025-13017-z.
对基于青蒿素的联合疗法产生耐药性，使得开发新型抗疟药物成为必要。本研究首次对靶向亲环蛋白的甾体四氧烷杂化物进行了计算研究，亲环蛋白是青蒿素耐药机制中涉及的一种关键蛋白。我们设计了一个由127种甾体 - 1,2,4,5 - 四氧烷杂化化合物组成的文库，该文库结合了甾体皂甙元（Δ - 薯蓣皂苷元 - 3 - 酮）和偕二氢过氧化物，并在八个平台上采用共识分子对接，以尽量减少算法特异性偏差。化合物A - CY - 9C成为主要候选物，在500纳秒的分子动力学模拟中表现出卓越的结合稳定性和有利的自由能态势。双重药效团机制——通过甾体成分破坏寄生虫胆固醇摄取，同时通过四氧烷部分诱导氧化应激——为对抗青蒿素耐药性提供了一种新策略。这种用甾体 - 四氧烷杂化物靶向亲环蛋白的一流方法为开发针对耐药菌株的下一代抗疟药物提供了一个有前景的基础。
在线版本包含可在10.1038/s41598 - 025 - 13017 - z获取的补充材料。
