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Despite their therapeutic relevance, the development of selective small-molecule inhibitors for these enzymes has been limited compared to other serine proteases. To address this, we implemented a fragment-based virtual screening (FBVS) strategy to identify chemically tractable starting points for the inhibition of KLK6 and KLK7. The computational workflow, combining structure-based docking tailored to serine protease active sites, was experimentally validated using in vitro enzymatic assays. Notably, the approach yielded hit rates (IC50 \u2264 100 \u03bcM) ranging from 4% (KLK7) to 21.6% (KLK6), underscoring both the robustness of the screening cascade and the druggability of these targets. Preliminary structure\u2013activity relationship analysis identified fragment 69 as a potent and ligand-efficient KLK6 inhibitor (IC50 = 2.1 \u03bcM, LE = 0.43). For KLK7, a distinct neutral 2-hydroxyquinoline fragment (38) was validated as a ligand-efficient hit (IC50 = 43.3 \u03bcM; LE = 0.46). Overall, this study demonstrates that kallikrein-related peptidases are amenable to fragment-based discovery and provides chemically simple, highly ligand-efficient fragments that serve as promising starting points for lead optimization targeting kallikrein-driven pathologies.<\/jats:p>","DOI":"10.1021\/acs.jcim.6c02059","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:06:16Z","timestamp":1785920776000},"page":"11389-11402","source":"Crossref","is-referenced-by-count":0,"title":["Fragment-Based\nDiscovery of KLK6 and KLK7 Inhibitors"],"prefix":"10.1021","volume":"66","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6195-4236","authenticated-orcid":true,"given":"Renato Ferreira","family":"de Freitas","sequence":"first","affiliation":[{"name":"Universidade Federal do ABC , , Rua Arcturus 3, Sa\u0303o Bernardo do Campo , ,","place":["Sa\u0303o Paulo, Brazil, 09606-070"]},{"name":"Universidade Federal de Ouro Preto , , Ouro Preto , ,","place":["Minas Gerais, Brazil, 35400-000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feryel","family":"Soualmia","sequence":"additional","affiliation":[{"name":"Adaptation and Ageing , , Dev2A , ,","place":["Paris, France, F-75005"]},{"name":"IBPS , , ,","place":["Paris, France, F-75005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rile\u0300s","family":"Boumali","sequence":"additional","affiliation":[{"name":"Adaptation and Ageing , , Dev2A , ,","place":["Paris, France, F-75005"]},{"name":"IBPS , , ,","place":["Paris, France, F-75005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmine","family":"Harrak","sequence":"additional","affiliation":[{"name":"Adaptation and Ageing , , Dev2A , ,","place":["Paris, France, F-75005"]},{"name":"IBPS , , ,","place":["Paris, France, F-75005"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1028-5113","authenticated-orcid":true,"given":"Chahrazade El","family":"Amri","sequence":"additional","affiliation":[{"name":"Adaptation and Ageing , , Dev2A , ,","place":["Paris, France, F-75005"]},{"name":"IBPS , , ,","place":["Paris, France, F-75005"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"issue":"3","key":"2026091409083246400_cit1","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1038\/nrd4534","article-title":"Unleashing\nthe Therapeutic Potential of Human Kallikrein-Related Serine Proteases","volume":"14","author":"Prassas","year":"2015","journal-title":"Nat. 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Sci."},{"issue":"11","key":"2026091409083246400_cit4","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1080\/21678707.2020.1857724","article-title":"Advances in\nUnderstanding of Netherton Syndrome and\nTherapeutic Implications","volume":"8","author":"Petrova","year":"2020","journal-title":"Expert Opin. Orphan\nDrugs"},{"issue":"16","key":"2026091409083246400_cit5","doi-asserted-by":"publisher","first-page":"4547","DOI":"10.1016\/j.bmcl.2013.06.039","article-title":"1,2,4-Triazole Derivatives as Transient\nInactivators of Kallikreins Involved in Skin Diseases","volume":"23","author":"Tan","year":"2013","journal-title":"Bioorg. Med. Chem. 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