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Journals / Doğu Karadeniz Sağlık Bilimleri Dergisi / 2025 / Cilt: 4 Sayı: 4

Evaluation of Approved Drugs' Prion Protein Binding Profiles Using a Drug Repurposing Approach

Onaylı İlaçların Prion Protein Bağlanma Profillerinin İlaç Yeniden Konumlandırma Yaklaşımı ile Değerlendirilmesi

Gülşah Aydın(ORDU UNIVERSITY)0000-0002-5376-0690
Pages
296–308
Publication Date
2025-11-30
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AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Confirmation of the findings with biophysical, cellular, and in vivo studies is important to clarify translational potential.

📌 3 Key Takeaways

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Objective & Hypothesis:Objective: Prion diseases are a critical neurodegenerative group with rapid progression, high mortality, and a lack of disease-modifying treatments.
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Key Findings & Data:The conversion of PrP^C to the infectious PrP^Sc isoform is central to pathogenesis, and conformational rearrangements at the β2–α2 loop and the H2–H3 interface play crucial roles in this conversion.
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Conclusion & Impact:Confirmation of the findings with biophysical, cellular, and in vivo studies is important to clarify translational potential.
🔬Design:Araştırma Makalesi
📍Scope:Comprehensive Sample
⚙️Variables:Prion hastalıkları · PrP Protein · Tucatinib

Abstract

Objective: Prion diseases are a critical neurodegenerative group with rapid progression, high mortality, and a lack of disease-modifying treatments. The conversion of PrP^C to the infectious PrP^Sc isoform is central to pathogenesis, and conformational rearrangements at the β2–α2 loop and the H2–H3 interface play crucial roles in this conversion. In this study, we evaluated the binding potential of clinically useful small molecules to this surface using a structure-based approach, hypothesizing that stabilizing these regions could slow misfolding. Method: The binding site encompassing the β2–α2 and H2–H3 regions of human PrP (PDB ID: 2LSB) was defined using the NMR-based globular domain. Twenty-five small molecules in clinical use were docking to this region with AutoDock Vina and ranked based on their relative binding free energies. Findings: Most ligands concentrated at -7.0 kcal/mol and more negative binding energies; This indicated that the target site was suitable for small molecule uptake. Tucatinib exhibited the strongest binding value (–8.03 kcal/mol) and showed compact localization at the β2–α2/H2–H3 transition region. Entrectinib, Ubrogepant, Atogepant, and Ribociclib also exhibited high-affinity binding with scores of –7.0 kcal/mol and above. Conclusion: Clinical molecules can be repositioned in prion diseases and may contribute to PrP stabilization by specifically targeting the β2–α2–H2–H3 interface. Tucatinib stands out for further validation based on its binding profile. Confirmation of the findings with biophysical, cellular, and in vivo studies is important to clarify translational potential.

Özet

Amaç: Prion hastalıkları, hızlı ilerleyişi, yüksek mortalitesi ve hastalık-modifiye edici tedavi eksikliğiyle kritik bir nörodejeneratif gruptur. Patogenezde PrP^C’nin bulaştırıcı PrP^Sc izoformuna dönüşümü merkezi olup, bu dönüşümde β2–α2 döngüsü ile H2–H3 arayüzündeki konformasyonel yeniden düzenlenme önemli rol oynar. Bu çalışmada, ilgili bölgeleri stabilize etmenin yanlış katlanmayı yavaşlatabileceği hipoteziyle, klinikte kullanılan küçük moleküllerin bu yüzeye bağlanma potansiyeli yapı-temelli yaklaşımla değerlendirildi. Yöntem: İnsan PrP’sinin (PDB ID: 2LSB) NMR tabanlı globüler domeni kullanılarak β2–α2 ve H2–H3 bölgelerini kapsayan bağlanma alanı tanımlandı. Klinik kullanımda olan 25 küçük molekül AutoDock Vina ile bu bölgeye doking yapılarak bağlanma serbest enerjileri üzerinden göreli sıralandı. Bulgular: Ligandların çoğu –7.0 kcal/mol ve daha negatif bağlanma enerjisinde yoğunlaştı; bu durum hedef bölgenin küçük molekül tutulumuna uygun olduğunu gösterdi. Tucatinib en güçlü bağlanma değerini (–8.03 kcal/mol) sergiledi ve β2–α2/H2–H3 geçiş bölgesinde kompakt yerleşim gösterdi. Entrectinib, Ubrogepant, Atogepant ve Ribociclib de –7.0 kcal/mol ve üzerindeki skorlarıyla yüksek afiniteli bağlanma sundu. Sonuç: Klinik moleküller prion hastalıklarında yeniden konumlandırılabilir ve özellikle β2–α2–H2–H3 arayüzünü hedefleyerek PrP stabilizasyonuna katkı sağlayabilir. Tucatinib, bağlanma profili doğrultusunda ileri doğrulama için öne çıkmaktadır. Bulguların biyofiziksel, hücresel ve in vivo çalışmalarla teyidi translasyonel potansiyelin netleştirilmesi açısından önemlidir.

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Cite This Article

Aydın, G. (2025). Evaluation of Approved Drugs' Prion Protein Binding Profiles Using a Drug Repurposing Approach. Doğu Karadeniz Sağlık Bilimleri Dergisi, Cilt: 4 Sayı: 4, 296–308. https://doi.org/10.59312/ebshealth.1821737

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