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However, identifying optimal electrophilic warheads and nucleophilic amino acids remains a major hurdle for TCI development. While covalent fragment libraries are efficient in the identification of reactive residues, their inherently weak and transient interactions often fail to address functionally relevant binding sites. Here, we combine the exploratory approach of covalent fragment screening with established inhibitor pharmacophores for covalent mapping of the tunnel allosteric site of the oncogenic phosphatase SHP2. Aryl sulfonyl fluoride (SF) fragments featuring pharmacophore elements to enhance noncovalent interactions (target\u2010biased fragments) covalently targeted lysine 492 (K492) in the tunnel binding site, while a conventional SF fragment library lacking these features was not reactive toward K492. Covalent engagement of K492 improved enzyme inhibition and provides a starting point for SHP2 TCI development. More broadly, this study underscores how noncovalent interactions direct covalent fragment binding and highlights target\u2010biased fragments as a complementary strategy to conventional covalent fragment libraries to identify suitable warheads and reactive amino acids in functionally relevant binding sites with minimal a priori knowledge of ligand pharmacophores.<\/jats:p>","DOI":"10.1002\/cbic.70310","type":"journal-article","created":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T06:24:17Z","timestamp":1777098257000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mapping the SHP2 Allosteric Pocket With Target\u2010Biased Covalent Fragments"],"prefix":"10.1002","volume":"27","author":[{"given":"Nina\u2010Louisa","family":"Efr\u00e9m","sequence":"first","affiliation":[{"name":"Medicinal Chemistry Leibniz\u2010Forschungsinstitut f\u00fcr Molekulare Pharmakologie (FMP)  Berlin Germany"},{"name":"Karlsruhe 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