YENİ TAKRİN VE HESPERETİN ANALOGLARI: ALZHEİMER HASTALIĞINDA POTANSİYEL ASETİLKOLİN ESTERAZ İNHİBİTÖRLERİNİN AYDINLATILMASI İÇİN TASARIM, MOLEKÜLER DOKİNG VE İN SİLİKO ADME ÇALIŞMALARI

Abstract

Amaç: Mevcut araştırma, Alzheimer hastalığını tedavi etmek için Tacrin ve Hesperetin yapılarından moleküler modifikasyonla yeni potansiyel moleküller tasarlamayı ve belirlemeyi amaçlamaktadır. Asetilkolinesteraz (AChE) enzimi hedef olarak seçilmiştir, çünkü AChE inhibitörleri demansın tedavisinde ve diğer semptomların hafifletilmesinde başarılı olmuştur.

Gereç ve Yöntem: Bu çalışmada, asetilkolinesteraz (AChE) inhibitörlerinin yapısal özelliklerinitemel alan iki seri yeni Takrin (T1-T9) ve Hesperetin(H1-H9) türevleri tasarlanmış ve AChE (PDB ID: 1DX4) üzerinde Anti-Alzheimer ilaç olarak potansiyel türevler belirlemek için ekstra hassasdoking uygulaması ile GLIDE kullanarak taranmıştır. Doking sonuçları (Glide skoru, XP skoru, doking skoru ve bağlanma etkileşimleri) standart ilaç, Takrin ile karşılaştırıldı.

Sonuç ve Tartışma: Doking sonuçlarından, T9'un tasarlanan bileşikler arasında en yüksek doking skoru gösterdiği bulundu. ADME özellikleri ayrıca Qikprop uygulaması kullanılarak da öngörülmüş, yukarıdaki çalışmalardan en yüksek AChE inhibisyonuna sahip potansiyel analoglar ve mükemmel farmakokinetik özellikleri tanımlanmıştır.

Keywords

• Alzheimer hastalığı (AD),asetilkolinesteraz inhibitörleri (AChE),glide,takrin

Novel Tacrine and Hesperetin analogues: Design, Molecular docking and in silico ADME studies to identify potential Acetyl choline esterase inhibitors for Alzheimer’s disease.

Abstract

Alzheimer’s disease is considered as most prevailing and common CNS disease found in elder population over 60 years of age. The early diagnosis of the disease prior to the occurrence of first behavioral symptom, dementia is difficult and hence the management of dementia and alleviation of other symptoms is the only available treatment for the AD. Acetyl cholinesterase inhibitors (AchE) are widely used in the treatment.   In this study two series of new Tacrine(T1-T9) and Hesperetin derivatives(H1-H9) on the basis of the structural characteristics of acetyl cholinesterase (AchE) inhibitors were designed and screened to identify potential analogues as Anti-Alzheimer drug on the AchE (PDB ID:1DX4)   using GLIDE employing extra-precision docking. The docking results Glide score, XPscore, docking score and binding interactions were compared with standard drug Tacrine. From the docking results it was found that T9 showed highest docking score among the designed compounds. The ADME properties also predicted using Qikprop application, from the above studies potential analogues with highest AchE inhibition and excellent pharmacokinetic properties were identified.

Keywords

• Alzheimer’s Disease (AD),Acetylcholine esterase inhibitors(AchE),Glide,tacrine

References

1. 1. Alzheimer’s Association. Alzheimer’s disease Facts and Figures (2018). Alzheimer’s Dement; 14(3), 367-429. Retrieved from https://www.alzheimersanddementia.com/article/S1552-5260(18)30041-4/abstract
2. 2. Ortman, J.M., Velkoff, V.A., Hogan, H. (2014). An Aging Nation: The Older Population in the United States, Current Population Reports, U.S. Census Bureau, Washington, D.C., 25-1140. Retieved from https://www.census.gov/prod/2014pubs/p25-1140.pdf.
3. 3. Haibin, L., Lirong, W., Weiwei, S., &Xiang-QunX. (2014). Advances in recent patent and clinical trial drug development for Alzheimer’s disease, Pharmaceutical Patent Analyst, 3(4), 429-447.
4. 4. Snezana, A., Kustrin, C., Kettle, D., &Morton, W. (2018). A molecular approach in drug development for Alzheimer’s disease, Biomedicine&Pharmacotherapy, 106, 553-565.
5. 5. Parhiz, H., Roohbakhsh, A., Soltani, F., Rezaee, R., & Iranshahi, M. (2014). Antioxidant and Anti-Inflammatory Properties of the Citrus Flavonoids Hesperidin and Hesperetin: An Updated Review of their Molecular Mechanisms and Experimental Models. Phytotherapy Research, 29(3), 323–331. doi: 10.1002/ptr.5256
6. 6. Hajialyani, M., Farzaei, M. H., Echeverría, J., Nabavi, S., Uriarte, E., & Sobarzo-Sánchez, E. (2019). Hesperidin as a Neuroprotective Agent: A Review of Animal and Clinical Evidence. Molecules, 24(3), 648. doi: 10.3390/molecules24030648
7. 7. Schrödinger Release 2017-3: Glide, Schrödinger, LLC, New York, NY, 2017.
8. 8. Schrödinger Release 2017-3: QikProp, Schrödinger, LLC, New York, NY, 2017.