{
  "abstract": "Human tissue kallikreins are serine proteases implicated in the pathogenesis of neurodegenerative diseases, skin disorders, and various cancers. 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 ≤ 100 μM) ranging from 4% (KLK7) to 21.6% (KLK6), underscoring both the robustness of the screening cascade and the druggability of these targets. Preliminary structure–activity relationship analysis identified fragment 69 as a potent and ligand-efficient KLK6 inhibitor (IC50 = 2.1 μM, LE = 0.43). For KLK7, a distinct neutral 2-hydroxyquinoline fragment (38) was validated as a ligand-efficient hit (IC50 = 43.3 μM; 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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "Renato Ferreira de Freitas"
    },
    {
      "name": "Feryel Soualmia"
    },
    {
      "name": "Rilès Boumali"
    },
    {
      "name": "Yasmine Harrak"
    },
    {
      "name": "Chahrazade El Amri"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3dr7thmxe65fb.bib",
  "cited_by": 0,
  "doi": "10.1021/acs.jcim.6c02059",
  "fulltext_url": null,
  "id": "3dr7thmxe65fb",
  "issns": [
    "1549-9596",
    "1549-960X"
  ],
  "landing_url": "https://hal.science/hal-05739951v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.chim"
    ],
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.chim.chem"
    ],
    [
      "hal",
      "1.sdv.bbm"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7172513877",
  "pdf_url": "https://hal.science/hal-05739951/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-05",
  "publisher": "American Chemical Society",
  "ris": "https://research.draconitic.com/paper/3dr7thmxe65fb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:29Z",
      "native_id": "hal-05739951",
      "source": "hal",
      "url": "https://hal.science/hal-05739951v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "hal:1.sdv.bbm",
      "subfield": "general"
    },
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    },
    {
      "field": "chemistry",
      "origin": "hal:0.chim",
      "subfield": "general"
    }
  ],
  "title": "Fragment-Based Discovery of KLK6 and KLK7 Inhibitors",
  "title_text": "Fragment-Based Discovery of KLK6 and KLK7 Inhibitors",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:29Z",
  "url": "https://research.draconitic.com/paper/3dr7thmxe65fb",
  "venue": "Journal of Chemical Information and Modeling",
  "versions": []
}