{
  "abstract": "We present a reproducible, reactivity-weighted covalent-screening workflow that separates molecular recognition, intrinsic electrophile reactivity, and matched host-protease covalent capture, and we validate it before applying it. Screening 1,012 South African Natural Compounds Database entries against falcipain-2 and falcipain-3, a warhead/β-accessibility cascade retained 185 compounds, and a consensus of recognition docking, uniform-mode covalent docking, MM-GBSA, DFT reactivity descriptors, and predicted developability prioritized SANC00867. A retrospective benchmark (256 falcipain-2 actives, 5,016 propertymatched decoys) shows recognition docking alone does not enrich covalent falcipain-2 actives (ROC-AUC 0.53), and that the covalent signal is carried by warhead reactivity, not recognition: adding warhead reactivity significantly improves retrieval over docking on both propertymatched and stringent warhead-matched decoy benchmarks (ROC-AUC 0.62 vs 0.56, DeLong p = 0.015 in the stringent test), while docking alone remains near-random throughout; covalent pose recovery is validated against a crystallographic vinyl-sulfone complex, and the dual-target ranking is robust to food-vacuole (pH 5.5) preparation (Spearman ρ = 0.77 and 0.97 for FP-2 and FP-3). Across capped para-substituted cinnamate models, global electrophilicity and the site-local β-carbon Fukui index diverge under strong electron withdrawal (4-NO2 raises global ω yet collapses the β-carbon f+ through LUMO localization), so warhead tuning is governed by local, not global, electrophilicity. A matched host-cathepsin covalent counter-screen shows SANC00867’s apparent selectivity does not survive receptor-normalized analysis, reported as a cross-target scoring result rather than a selectivity claim. The workflow thus delivers a validated, transparent prioritization framework and a chemically interpretable design rule, with all inputs, scripts, and settings deposited for reuse.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemical Sciences",
    "Lead City University",
    "Department of Chemistry",
    "University of Ibadan"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Olaniyi Victor Olaniru",
      "orcid": "0009-0008-9853-6335"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Clement Odunayo Ajiboye"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0fqjfx1pyzr81.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15008280/v1",
  "fulltext_url": null,
  "id": "0fqjfx1pyzr81",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008280/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7208774865",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15008280/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-03",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/0fqjfx1pyzr81.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.26434/chemrxiv.15008280",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15008280/v2"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Reactivity Over Recognition: Covalent Screening of Natural Products against Falcipain-2 and Falcipain-3",
  "title_text": "Reactivity Over Recognition: Covalent Screening of Natural Products against Falcipain-2 and Falcipain-3",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:21Z",
  "url": "https://research.draconitic.com/paper/0fqjfx1pyzr81",
  "venue": "ChemRxiv",
  "versions": []
}