{
  "abstract": "The Size‑Independent Enthalpic Efficiency (SIHE) metric normalizes binding enthalpy by molecular size and is used to compare ligands across different sizes. Re‑analyzing the Ferenczy dataset after cleaning and stratification reveals that the aggregate data exhibit an unphysical compensation slope of –1.04, which resolves into plausible slopes of –0.86 (General) and –0.75 (HIV) upon stratification. For non‑HIV targets, pKH_90 shows no meaningful correlation with molecular size (linear R2 = 0.12; power law R2 = 0.13, exponent –0.23). SIHE achieves size independence trivially because pKH is already size‑independent. The apparent size dependence in the original analysis is driven by HIV‑1 protease inhibitors, which are confined to HA = 35–50 and exhibit a distinct entropy‑driven, endothermic binding mode. Structural analysis attributes this entropy‑driven behavior to HIV‑1 protease’s non‑canonical binding site architecture (interfacial pocket, aromatic‑poor/Asp‑rich composition, glycine‑rich flap network). Formal statistical comparison (Hotelling's T2 p < 10-140) and geometric ellipse overlap (2.6%) confirm that the two subsets are largely separate. SIHE should not be used as a general metric for enthalpic efficiency.",
  "abstract_shown": true,
  "affiliations": [
    "Qianhangjiang Pharmaceutical Co, Ltd, 988 Yangshan Road, Haining, Zhejiang, 314408"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Xuliang Jiang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b6nfa0ywtmft0.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010701/v1",
  "fulltext_url": null,
  "id": "b6nfa0ywtmft0",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010701/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",
      "1606|thermodynamics and calorimetric analyses"
    ]
  ],
  "openalex": "W7223038832",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010701/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-20",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/b6nfa0ywtmft0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010701",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010701/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "openalex:1606|thermodynamics and calorimetric analyses",
      "subfield": "physical"
    }
  ],
  "title": "The Ferenczy Dataset Revisited: How HIV Protease Inhibitors Created an Illusion of Universal Size Dependence in Ligand Binding",
  "title_text": "The Ferenczy Dataset Revisited: How HIV Protease Inhibitors Created an Illusion of Universal Size Dependence in Ligand Binding",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/b6nfa0ywtmft0",
  "venue": "ChemRxiv",
  "versions": []
}