Amilorid'in İlaç Benzerliği, Farmakokinetik Profili, Toksisite Parametreleri ve Anti-Alzheimer Aktivitesinin Belirlenmesi: Ayrıntılı Bir in silico Araştırma

Abstract

Amaç: Alzheimer hastalığı (AH), amiloid-β birikimi ve sinaptik disfonksiyon da dahil olmak üzere karmaşık moleküler mekanizmalarla karakterize edilen ilerleyici bir nörodejeneratif bozukluktur. Bu bağlamda, bu çalışma, amilorid ve memantinin ASIC ile etkileşimleri, farmakokinetik ve toksisite ile ilgili özellikleri açısından karşılaştırmalı bir in silico değerlendirmesini yapmayı amaçlamıştır. Materyal ve Metot: Amilorid ve memantinin yapısal ve farmakokinetik özellikleri, moleküler kenetlenme, ADME tahmini ve toksisite profillemesi de dahil olmak üzere in silico yaklaşımlar kullanılarak değerlendirilmiştir. Moleküler kenetlenme analizleri, Molegro Virtual Docker kullanılarak ASIC reseptörüne (PDB ID: 2QTS) karşı gerçekleştirilmiştir. İlaç benzerliği ve farmakokinetik parametreler, yerleşik hesaplama platformlarına dayanarak değerlendirilmiş ve toksisite uç noktaları in silico toksisite modelleri kullanılarak tahmin edilmiştir. Bulgular: Kenetlenme analizi, amiloridin memantine kıyasla ASIC reseptörüne karşı daha yüksek tahmini bağlanma afinitesi sergilediğini göstermiştir. Her iki bileşik de Lipinski'nin beş kuralına uygunluk göstererek kabul edilebilir ilaç benzeri özellikler sergiledi. Bilgisayar ortamında yapılan ADME tahminleri, özellikle kan-beyin bariyeri geçirgenliği açısından farmakokinetik davranışta farklılıklar ortaya koydu; amilorid, memantine kıyasla merkezi sinir sistemine daha az nüfuz etti. Toksisite tahminleri, her iki bileşiğin de farklı toksisite uç noktalarında değişen olasılıklarla karışık güvenlik profillerine sahip olduğunu gösterdi. Sonuç: Mevcut bilgisayar ortamındaki bulgular, amiloridin hesaplamalı koşullar altında memantine kıyasla ASIC reseptörüyle daha olumlu etkileşime girebileceğini düşündürmektedir. Bununla birlikte, kullanılan yöntemlerin tahmine dayalı doğası göz önüne alındığında, bu sonuçlar dikkatli bir şekilde yorumlanmalıdır. Genel olarak, amilorid, Alzheimer hastalığının ASIC ile ilgili mekanizmalarında daha ileri deneysel araştırmalar için potansiyel bir öncü bileşik olabilir.

Keywords

• Alzheimer hastalığı
• Amilorid
• Asit duyarlı iyon kanalı
• In silico metot

Supporting Institution

Bu çalışma, Tokat Gaziosmanpaşa Üniversitesi Bilimsel Araştırma Koordinasyon Birimi tarafından desteklenmiştir (Hibre No:2025/76)

Ethical Statement

Çalışmamızda in silico yöntemi kullanıldığı için etik komite onayı alınmadı.

Thanks

Bu araştırmaya katılan tüm deneycilerin iş birliğini takdir ediyoruz.

The Determination of Druglikeness, Pharmacokinetic Profile, Toxicity Parameters, and Anti-Alzheimer Activity of Amiloride: A Detailed in silico Investigation

Abstract

Objective: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by complex molecular mechanisms, including amyloid-β accumulation and synaptic dysfunction. In this context, the present study aimed to perform a comparative in silico evaluation of amiloride and memantine in terms of their interactions with ASIC, along with their pharmacokinetic and toxicity-related properties. Materials and Methods: The structural and pharmacokinetic properties of amiloride and memantine were assessed using in silico approaches, including molecular docking, ADME prediction, and toxicity profiling. Molecular docking analyses were performed against the ASIC receptor (PDB ID: 2QTS) using Molegro Virtual Docker. Drug-likeness and pharmacokinetic parameters were evaluated based on established computational platforms, and toxicity endpoints were predicted using in silico toxicity models. Results: Docking analysis indicated that amiloride exhibited a higher predicted binding affinity for the ASIC receptor than memantine. Both compounds complied with Lipinski’s rule of five, suggesting acceptable drug-likeness. In silico ADME predictions revealed differences in pharmacokinetic behavior, particularly in blood–brain barrier permeability, with amiloride showing limited central nervous system penetration compared to memantine. Toxicity predictions suggested that both compounds possess mixed safety profiles, with varying probabilities across different toxicity endpoints. Conclusion: The present in silico findings suggest that amiloride may interact more favorably with the ASIC receptor compared to memantine under computational conditions. However, given the predictive nature of the employed methods, these results should be interpreted cautiously. Overall, amiloride may represent a potential lead compound for further experimental investigation in ASIC-related mechanisms of Alzheimer’s disease.

Keywords

• Acid-sensitive ion channel
• Alzheimer's disease
• Amiloride
• In silico method

Supporting Institution

This study was supported by Tokat Gaziosmanpaşa University Scientific Research Coordination Unit (Grant No:2025/76)

Ethical Statement

Since the in silico method was used in our study, ethics committee approval was not obtained.

Thanks

We appreciate the cooperation of all the experimenters who participated in this research.

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