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The S1P (sphingosine-1-phosphate) pathway, involved in cell survival, proliferation, and migration, plays a critical role in NHL pathogenesis. Targeting S1PR1, the receptor for S1P, may provide a therapeutic strategy for NHL. The primary objective of this study was to identify and evaluate the efficacy of S1P analogues against the S1PR1 receptor through computational methods and experimental validation. The crystal structure of S1PR1 was obtained from the Protein Data Bank, and computational methods, including molecular docking, QSAR modeling, and machine learning techniques, were employed to screen 779 S1P analogues. The most promising compounds were further analyzed through molecular dynamics simulations. In vitro, Raji cells were treated with the potent analogue CHEMBL1540377. MTT assay and colony formation assays were used to evaluate cell viability and proliferation. Additionally, apoptosis and necrosis were assessed by AO\/EB staining. Computational studies identified several analogues with high binding affinities to S1PR1, including CHEMBL1540377. Molecular dynamics simulations confirmed the stability and binding of CHEMBL1540377 with S1PR1. In vitro assays demonstrated that CHEMBL1540377 significantly reduced cell viability and inhibited colony formation in Raji cells. AO\/EB staining revealed that the compound induced both apoptosis and necrosis in the treated cells. This study identifies CHEMBL1540377 as a potent analogue targeting S1PR1 for NHL therapy. The combination of computational and experimental findings provides a strong foundation for future research and potential clinical application of S1P analogues in treating NHL.<\/jats:p>","DOI":"10.1038\/s41598-025-25129-7","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T09:37:42Z","timestamp":1764322662000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Computational screening and in vitro evaluation of sphingosine-1-phosphate analogues as therapeutics for Non-Hodgkin\u2019s lymphoma"],"prefix":"10.1038","volume":"15","author":[{"given":"Ahmed Abdullah","family":"Al Awadh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"issue":"4","key":"25129_CR1","first-page":"1834","volume":"9","author":"R Singh","year":"2020","unstructured":"Singh, R. et al. 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