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<p>Tau-protein aggregation is a central pathological feature of Alzheimer’s disease, so blocking fibril growth is an attractive therapeutic goal. We curated a high-quality set of 289 literature IC<sub>50 </sub> measurements for human-tau aggregation and trained a stacked-ensemble QSAR model (SVR + RF + XGB) that achieves fivefold CV Q<sup>2</sup> = 0.63, external R<sup>2</sup> = 0.57 and RMSE = 0.73 log-units. Applicability-domain analysis revealed no high-influence outliers in the calibration set, and a 5-nearest-neighbour density test confirmed that each of sixteen previously unreported 1,2,4-triazole–naphthalene derivatives (TND, TND-1…TND-15) lies in locally populated chemical space, albeit at the edge of the global domain. The model predicts pIC<sub>50 </sub> = 6.75–7.53 (IC<sub>50 </sub> ≈ 30–177&#xa0;nM), nominating TND-9, TND-15 and TND-5 as top-ranked candidates based on predicted potency. Nearly all TNDs fall within the BBB window (MW ≈ 350–450&#xa0;Da, TPSA &lt; 90 Å<sup>2</sup>); most obey cLogP ≤ 5, and the few slightly above still map to the BOILED-Egg CNS-positive zone. Retrospective docking against phosphorylated-tau fibrils (PDB ID 6HRF) highlighted TND, TND-5 and TND-14 with sub-micromolar predicted affinity, forming key contacts in the microtubule-binding cleft. These docking results support binding plausibility rather than quantitative aggregation inhibition. TND-8, although highly ranked by docking, was deprioritised owing to low predicted GI absorption. Physicochemical and CNS-oriented ADMET filters further support developability of the top leads. The integrated workflow—combining rigorously validated QSAR, structure-based docking on the 6HRF polymorph and developability profiling—provides an open-source blueprint for tau-aggregation inhibitor discovery. Consensus ranking prioritises TND-5 for immediate in-silico follow-up, with TND, TND-14, TND-9 and TND-15 as secondary leads.</p>

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Integrating ensemble machine-learning and fibril docking to discover potent, novel triazole–naphthalene tau-aggregation inhibitors

  • 期刊论文

  • 发表日期：

    2026年3月4日

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  • Poulami Saha,
  • Anuja Chouhan

摘要

Tau-protein aggregation is a central pathological feature of Alzheimer’s disease, so blocking fibril growth is an attractive therapeutic goal. We curated a high-quality set of 289 literature IC50  measurements for human-tau aggregation and trained a stacked-ensemble QSAR model (SVR + RF + XGB) that achieves fivefold CV Q2 = 0.63, external R2 = 0.57 and RMSE = 0.73 log-units. Applicability-domain analysis revealed no high-influence outliers in the calibration set, and a 5-nearest-neighbour density test confirmed that each of sixteen previously unreported 1,2,4-triazole–naphthalene derivatives (TND, TND-1…TND-15) lies in locally populated chemical space, albeit at the edge of the global domain. The model predicts pIC50  = 6.75–7.53 (IC50  ≈ 30–177 nM), nominating TND-9, TND-15 and TND-5 as top-ranked candidates based on predicted potency. Nearly all TNDs fall within the BBB window (MW ≈ 350–450 Da, TPSA < 90 Å2); most obey cLogP ≤ 5, and the few slightly above still map to the BOILED-Egg CNS-positive zone. Retrospective docking against phosphorylated-tau fibrils (PDB ID 6HRF) highlighted TND, TND-5 and TND-14 with sub-micromolar predicted affinity, forming key contacts in the microtubule-binding cleft. These docking results support binding plausibility rather than quantitative aggregation inhibition. TND-8, although highly ranked by docking, was deprioritised owing to low predicted GI absorption. Physicochemical and CNS-oriented ADMET filters further support developability of the top leads. The integrated workflow—combining rigorously validated QSAR, structure-based docking on the 6HRF polymorph and developability profiling—provides an open-source blueprint for tau-aggregation inhibitor discovery. Consensus ranking prioritises TND-5 for immediate in-silico follow-up, with TND, TND-14, TND-9 and TND-15 as secondary leads.