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Sci.","IJMS"],"abstract":"<jats:p>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\u2013activity relationship resource integrating 3093 unique inhibitors (consensus pIC50 range 2.00\u20138.52; 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 \u22650.6 indicates that the sampled PAD4 SAR landscape is predominantly smooth: only 94 pairs meeting the stringent activity-cliff criterion (Tanimoto \u2265 0.8; |\u0394pIC50| \u2265 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.<\/jats:p>","DOI":"10.3390\/ijms27188302","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T13:18:26Z","timestamp":1790860706000},"page":"8302","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PAD4-DB: A Curated Structure\u2013Activity Resource Reveals Hub-Organized Activity Cliffs and Scaffold-Dependent SAR Ruggedness in PAD4 Inhibitors"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5042-2947","authenticated-orcid":false,"given":"Nidhal","family":"Tarhouni","sequence":"first","affiliation":[{"name":"Laboratory of Enzyme Engineering and Microbiology, Engineering National School of Sfax (ENIS), University of Sfax, P.O. Box 1173, Sfax 3038, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4540-2399","authenticated-orcid":false,"given":"Ahmed","family":"Bayoudh","sequence":"additional","affiliation":[{"name":"Laboratory of Enzyme Engineering and Microbiology, Engineering National School of Sfax (ENIS), University of Sfax, P.O. Box 1173, Sfax 3038, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4588-5685","authenticated-orcid":false,"given":"Amira","family":"Mahfoudhi","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Enzymatic Engineering of Lipases, Engineering National School of Sfax (ENIS), University of Sfax, Sfax 3038, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0671-4018","authenticated-orcid":false,"given":"Bilel","family":"Hadrich","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, College of Engineering, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11432, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6756-604X","authenticated-orcid":false,"given":"Karim","family":"Kriaa","sequence":"additional","affiliation":[{"name":"Department of Chemical Engineering, College of Engineering, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11432, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9139-4233","authenticated-orcid":false,"given":"Imen","family":"Kallel","sequence":"additional","affiliation":[{"name":"Research Laboratory of Environmental Toxicology-Microbiology and Health (LR17ES06), Faculty of Sciences, University of Sfax, Sfax 3038, Tunisia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1083\/jcb.200806072","article-title":"Histone Hypercitrullination Mediates Chromatin Decondensation and Neutrophil Extracellular Trap Formation","volume":"184","author":"Wang","year":"2009","journal-title":"J. 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