{
  "abstract": "Peptidylarginine deiminase 4 (PAD4) is an increasingly prominent therapeutic target in oncology, inflammatory disease, and neutrophil extracellular trap (NET)-associated pathologies, yet public bioactivity data for PAD4 inhibitors remain fragmented across multiple repositories with substantial redundancy and inconsistent annotation. Here, we present PAD4-DB, a curated structure–activity relationship resource integrating 3093 unique inhibitors (consensus pIC50 range 2.00–8.52; median 6.84) from PubChem, ChEMBL, and BindingDB through a reproducible pipeline encompassing structure standardization, activity normalization, source-independence assessment, and deduplication. Quantitative analysis of 358,416 compound pairs with Tanimoto similarity ≥0.6 indicates that the sampled PAD4 SAR landscape is predominantly smooth: only 94 pairs meeting the stringent activity-cliff criterion (Tanimoto ≥ 0.8; |ΔpIC50| ≥ 2.0) were identified, representing 0.026% of all related pairs and 0.78% of the 12,071 cliff-candidate pairs. Of these, 80 (85.1%) received structural support from matched molecular pair (MMP) analysis. Severe cliffs were non-randomly distributed, with four hub compounds collectively accounting for 53.2% of all severe cliff pairs, while 96.8% of multi-member scaffold series remained completely smooth. Provenance analysis further showed that 82.9% of the dataset was classified as pipeline-dependent under the provenance-scoring framework across repositories rather than independent source measurements, underscoring the importance of provenance-aware confidence weighting in downstream modeling. PAD4-DB therefore provides a reproducible foundation for PAD4 inhibitor discovery and a curated benchmark for evaluating similarity-based and machine-learning approaches in a chemically structured SAR landscape containing rare but highly concentrated activity cliffs.",
  "abstract_shown": true,
  "affiliations": [
    "Laboratory of Enzyme Engineering and Microbiology, Engineering National School of Sfax (ENIS), University of Sfax, P.O. Box 1173, Sfax 3038, Tunisia",
    "Laboratory of Biochemistry and Enzymatic Engineering of Lipases, Engineering National School of Sfax (ENIS), University of Sfax, Sfax 3038, Tunisia",
    "Department of Chemical Engineering, College of Engineering, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11432, Saudi Arabia",
    "Research Laboratory of Environmental Toxicology-Microbiology and Health (LR17ES06), Faculty of Sciences, University of Sfax, Sfax 3038, Tunisia"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Nidhal Tarhouni",
      "orcid": "0000-0001-5042-2947"
    },
    {
      "affs": [
        0
      ],
      "name": "Ahmed Bayoudh",
      "orcid": "0000-0003-4540-2399"
    },
    {
      "affs": [
        1
      ],
      "name": "Amira Mahfoudhi",
      "orcid": "0000-0003-4588-5685"
    },
    {
      "affs": [
        2
      ],
      "name": "Bilel Hadrich",
      "orcid": "0000-0002-0671-4018"
    },
    {
      "affs": [
        2
      ],
      "name": "Karim Kriaa",
      "orcid": "0000-0001-6756-604X"
    },
    {
      "affs": [
        3
      ],
      "name": "Imen Kallel",
      "orcid": "0000-0001-9139-4233"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/bxp286qtx6jp7.bib",
  "cited_by": 0,
  "doi": "10.3390/ijms27188302",
  "fulltext_url": null,
  "id": "bxp286qtx6jp7",
  "issns": [
    "1422-0067"
  ],
  "landing_url": "https://www.mdpi.com/1422-0067/27/18/8302",
  "language": null,
  "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": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7214474162",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-17",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/bxp286qtx6jp7.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:55Z",
      "native_id": "10.3390/ijms27188302",
      "source": "crossref",
      "url": "https://www.mdpi.com/1422-0067/27/18/8302"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "issn:1422-0067",
      "subfield": "general"
    }
  ],
  "title": "PAD4-DB: A Curated Structure–Activity Resource Reveals Hub-Organized Activity Cliffs and Scaffold-Dependent SAR Ruggedness in PAD4 Inhibitors",
  "title_text": "PAD4-DB: A Curated Structure–Activity Resource Reveals Hub-Organized Activity Cliffs and Scaffold-Dependent SAR Ruggedness in PAD4 Inhibitors",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:55Z",
  "url": "https://research.draconitic.com/paper/bxp286qtx6jp7",
  "venue": "International Journal of Molecular Sciences",
  "versions": []
}