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The significant development is hindered by the multi-drug resistance and poor patient compliance. PIK3CA gene mutation is one of the important causes of TNBC, which causes dysregulation of the cell cycle and cell proliferation. PI3K\u03b1 selective inhibition can decrease the TNBC by a significant level with minimal off-target effects. Novel compounds with high selectivity towards PI3K\u03b1 are crucial for treating TNBC. After extensive literature analysis, it was observed that fragment-based drug discovery, combined with structure-based virtual screening and bioisosteric replacement strategy, could provide a novel way for hit-to-lead optimization. The present study focussed on the fragment-based direct linking of 11269 moieties of the ChemDiv fragment library, - to generate novel moieties and further screened them using molecular docking, MMGBSA, and target selectivity analysis. Further, the top 2 moieties \u2013 Djh1 and Djh2 were selected after MMGBSA analysis and target selectivity prediction towards kinase. Further induced fit docking (IFD) analysis, DFT analysis, and MD simulation were employed to establish that \u2013 Djh1 and Djh2 could act as potential hit molecules for selective inhibition of PI3K\u03b1. Further bioisosteric replacement, docking analysis, and target selectivity analysis were performed with the bioisosteres. The top two bioisosteres of Djh1 \u2013 Compound 10, Compound 06 represented excellent efficacy and selectivity towards PI3K\u03b1 in the treatment of TNBC after analysis of ADMET analysis. Further, in vitro and in vivo analysis might prove the effectiveness of the hit compounds.<\/jats:p>","DOI":"10.1038\/s41598-024-83030-1","type":"journal-article","created":{"date-parts":[[2025,1,13]],"date-time":"2025-01-13T23:07:48Z","timestamp":1736809668000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Exploring target selectivity in designing and identifying PI3K\u03b1 inhibitors for triple negative breast cancer with fragment-based and bioisosteric replacement approach"],"prefix":"10.1038","volume":"15","author":[{"given":"Debojyoti","family":"Halder","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shreya","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R. 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