The Ferenczy Dataset Revisited: How HIV Protease Inhibitors Created an Illusion of Universal Size Dependence in Ligand Binding
- 1Qianhangjiang Pharmaceutical Co, Ltd, 988 Yangshan Road, Haining, Zhejiang, 314408
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.
Related
- Repurposing HIV Protease Inhibitors as Antifungal Chemosensitizers Against Multidrug Resistant Candida auris: Promise, Limitations, and Translational Challenges
- Novel inhibitors of HSV-1 protease effective in vitro and in vivo
- Identification and Experimental Validation of Repurposable Drugs Targeting the Essential ClpP1 Protease of Mycobacterium tuberculosis
- Joining Two Perspectives of the Proteome with the Trypsin+HTA Protease Workflow
- Beyond the catalytic serine: selective protease engagement with covalent macrocyclic activity-based probes
BibTeX
@misc{jiang2026ferenczy,
title = {{The Ferenczy Dataset Revisited: How HIV Protease Inhibitors Created an Illusion of Universal Size Dependence in Ligand Binding}},
author = {Xuliang Jiang},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010701/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010701/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - The Ferenczy Dataset Revisited: How HIV Protease Inhibitors Created an Illusion of Universal Size Dependence in Ligand Binding
AU - Xuliang Jiang
PY - 2026
DA - 2026/10/20
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010701/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010701/v1
AB - 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.
ER -