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Computational Approaches for Drug Repurposing in Alzheimer's Disease

Year 2022, Volume: 25 Issue: Ek Sayı 2, 307 - 315, 30.12.2022

Zaid Jaafar Awad Al-nuaimi Abuzer Çelekli Tugba Taskın Tok

https://doi.org/10.18016/ksutarimdoga.vi.1092038

Abstract

Alzheimer's disease is a progressive age-related brain disorder. It causes gradual memory loss, changes in personality traits, confusion, impaired thinking, and mood changes Acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors have been chosen for the treatment of Alzheimer’s disease. Dual cholinesterase inhibitors have become a new hotspot in the investigation of anti-Alzheimer's drugs. The current study was designed to identify inhibitors for both AChE and BuChE enzymes using computational approaches to accelerate the process of identifying an effective treatment for Alzheimer. From the available drugs, we selected families of the aspirin and imatinib. After the adoption of molecular docking, we found that fendosal from aspirin group and Flumatinib from the Imatinib group are the most active compounds. The docking scores for fendosal was -8.160 kcal/mol against AChE while Flumatinib had -9.433 kcal/mol and -9.541 kcal/mol scores with BuChE and AChE, respectively. The 10 ns molecular dynamics simulation for fendosal and flumatinib against AChE and BuChE was performed to evaluate the drug's ability to remain stable within the binding sites of AChE and BuChE with the aid of RMSD and RMSF plots. These results revealed that Flumatinib and fendosal are good inhibitors for both BuChE and AChE, which could be used in vivo and in vitro studies to improve outcomes.

Keywords

Aspirin Imatinib Acetylcholinesterase Butyrylcholinesteras Molecular docking

References

  • Abraham MJ, Murtola T, Schulz R, Páll S, Smith J C et al. 2015. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1: 19-25. https://doi.org/10.1016/ j.softx.2015.06.001
  • Al-Khafaji K, Taskin Tok T 2021a. Understanding the mechanism of Amygdalin’s multifunctional anti-cancer action using a computational approach. Journal of Biomolecular Structure and Dynamics, 39: 1600-1610. https://doi.org/10.1080/07391102.2020.1736159.
  • Al-Khafaji K, Al-Duhaidahawi D, Taskin Tok T 2021b. Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2. Journal of Biomolecular Structure and Dynamics, 39: 3387-3395. https://doi.org/10.1080/ 07391102.2020.1764392
  • Birks JS, Evans JG 2015. Rivastigmine for Alzheimer’s disease. Cochrane Database of Systematic Reviews, 4: 1-144. https://doi.org/ 10.1002/14651858.CD001191.pub3
  • Brunton L, Chabner BA, Knollmann BC 2011. Goodman and Gilman’s the pharmacological basis of therapeutics. Twelfth,New York, NY: McGraw-Hill.
  • Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić, AM, Vasić, VM (2013). Acetylcholinesterase inhibitors: pharmacology and toxicology. Current Neuropharmacology, 11(3): 315-335. https:// doi.org/10.2174/1570159X11311030006
  • Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB et al. 2012. Drug repositioning for Alzheimer’s disease. Nature Reviews Drug Discovery, 11(11): 833-846. https://doi:10.1038/nrd3869
  • Deardorff WJ, Grossberg GT 2019. Behavioral and psychological symptoms in Alzheimer’s dementia and vascular dementia. In Handbook of Clinical Neurology (1st ed., Vol. 165). Elsevier B.V. 165: 5-32 https://doi.org/10.1016/B978-0-444-64012-3.00002-2.
  • Essmann U, Perera L, Berkowitz ML, Darden T, Lee H et al. 1995. A smooth particle mesh Ewald method. The Journal of Chemical Physics, 103(19): 8577-8593. https://doi.org/10.1063/1.470117
  • Gaussian 09, Revision E.01, Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Mennucci B., Petersson G. A., et. al. Gaussian, Inc., Wallingford CT, 2009.
  • Gauthier S, Rosa-Neto P, Morais JA, Webster C 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
  • Giacobini E 2003. Cholinesterases: new roles in brain function and in Alzheimer’s disease. Neurochemical Research, 28(3): 515–522. https://doi.org/10.1023/A:1022869222652
  • Greig NH, Lahiri DK, Sambamurti K 2002. Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. International Psychogeriatrics, 14: 77-91. https://doi.org/ 10.1017/S1041610203008676
  • Jellinger, KA 2010. Basic mechanisms of neurodegeneration: a critical update. Journal of Cellular and Molecular Medicine, 14(3): 457-487. https://doi.org/10.1111/j.1582-4934.2010.01010.x
  • Kim JH, Thao NP, Han YK, Lee YS, Luyen BT T et al. 2018. The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1): 1174-1180. https://doi.org/10.1080/ 14756366.2018.1491847
  • Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D, Campos-Peña V 2014. Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer’s disease? Oxidative Medicine and Cellular Longevity, 2014: 497802. https://doi.org/10.1155/2014/497802.
  • Mendez MF 2012. Early-onset Alzheimer’s disease: nonamnestic subtypes and type 2 AD. Archives of Medical Research, 43(8): 677-685. https://doi.org/ 10.1016/j.arcmed.2012.11.009
  • Mendiola-Precoma J, Rodríguez-Cruz A, García-Alcocer G 2016. The Etiology of Alzheimer’s Disease. 1–14. https://doi.org/10.1155/ 2016/2589276
  • Ravindranath PA, Forli S, Goodsell DS, Olson AJ, Sanner MF 2015. AutoDockFR: advances in protein-ligand docking with explicitly specified binding site flexibility. PLoS Computational Biology, 11(12): e1004586. https://doi.org/10.1371/ journal.pcbi.1004586
  • Revett TJ, Baker GB, Jhamandas J, Kar S 2013. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. Journal of Psychiatry and Neuroscience, 38(1): 6-23. doi: 10.1503/jpn.110190
  • Trott O, Olson AJ 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2): 455-461.
  • Van Cauwenberghe C, Van Broeckhoven C, Sleegers K 2016. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genetics in Medicine, 18(5): 421-430. https://doi.org/10.1038/gim.2015.117
  • Vos T, Allen C, Arora M, Barber RM, Bhutta ZA et al. 2016. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053): 1545-1602. https://doi.org/10.1016/S0140-6736(16)31678-6
  • Wittenauer BR, Smith L 2013. Priority Medicines for Europe and the World " A Public Health Approach to Innovation " Update on 2004 Background Paper. Who, December.
  • Zhao QF, Tan L, Wang HF, Jiang T, Tan MS et al. 2016. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. Journal of Affective Disorders, 190: 264-271. https://doi.org/10.1016/ j.jad.2015.09.069

Alzheimer Hastalığında İlacın Yeniden Kullanım İçin Hesaplamalı Yaklaşımlar

Year 2022, Volume: 25 Issue: Ek Sayı 2, 307 - 315, 30.12.2022

Zaid Jaafar Awad Al-nuaimi Abuzer Çelekli Tugba Taskın Tok

https://doi.org/10.18016/ksutarimdoga.vi.1092038

Abstract

Alzheimer hastalığı, ilerleyici, yaşa bağlı bir beyin hastalığıdır. Kademeli hafıza kaybına, kişilik özelliklerinde değişikliklere, kafa karışıklığına, düşünme bozukluğuna ve ruh hali değişikliklerine neden olur. Alzheimer hastalığının tedavisi için asetilkolinesteraz (AChE) ve butirilkolinesteraz (BuChE) inhibitörü seçilmiştir. Çift kolinesteraz inhibitörleri, anti-Alzheimer ilaçlarının araştırılmasında yeni bir etkin nokta haline geldi. Bu çalışma, Alzheimer için etkili bir tedavi tanımlama sürecini hızlandırmak için hesaplama yaklaşımlarını kullanarak AChE ve BuChE enzimlerine yönelik inhibitörlerin belirlemesi için tasarlanmıştır. Mevcut ilaçlardan aspirin ve imatinib aileleri seçilmiştir. Moleküler yerleştirmenin benimsenmesinden sonra, aspirin grubundan fendosalın ve Imatinib grubundan flumatinib'in en etkin bileşikler olduğu bulunmuştur. Fendosal için kenetlenme skorları AChE'ye karşı -8,160 kcal/mol iken Flumatinib BuChE ve AChE ile sırasıyla -9,433 kcal/mol ve -9.541 kcal/mol skorlarına sahip olmuştur. AChE ve BuChE'ye karşı fendosal ve flumatinib için 10 ns moleküler dinamik simülasyonu, RMSD ve RMSF grafiklerinin yardımıyla ilacın AChE ve BuChE'nin bağlanma bölgeleri içinde stabil kalma kabiliyetini değerlendirmek için yapılmıştır. Bu sonuçlar, Flumatinib ve fendosal'ın hem BuChE hem de AChE için iyi bir inhibitör olduğunu ortaya koymuş olup sonuçların geliştirilmesi için in vivo ve in vitro çalışmaların kullanılabilir.

Keywords

Aspirin Imatinib Asetilkolin esteraz Butirilkolin esteraz Moleküler yerleştirme

References

  • Abraham MJ, Murtola T, Schulz R, Páll S, Smith J C et al. 2015. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX, 1: 19-25. https://doi.org/10.1016/ j.softx.2015.06.001
  • Al-Khafaji K, Taskin Tok T 2021a. Understanding the mechanism of Amygdalin’s multifunctional anti-cancer action using a computational approach. Journal of Biomolecular Structure and Dynamics, 39: 1600-1610. https://doi.org/10.1080/07391102.2020.1736159.
  • Al-Khafaji K, Al-Duhaidahawi D, Taskin Tok T 2021b. Using integrated computational approaches to identify safe and rapid treatment for SARS-CoV-2. Journal of Biomolecular Structure and Dynamics, 39: 3387-3395. https://doi.org/10.1080/ 07391102.2020.1764392
  • Birks JS, Evans JG 2015. Rivastigmine for Alzheimer’s disease. Cochrane Database of Systematic Reviews, 4: 1-144. https://doi.org/ 10.1002/14651858.CD001191.pub3
  • Brunton L, Chabner BA, Knollmann BC 2011. Goodman and Gilman’s the pharmacological basis of therapeutics. Twelfth,New York, NY: McGraw-Hill.
  • Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić, AM, Vasić, VM (2013). Acetylcholinesterase inhibitors: pharmacology and toxicology. Current Neuropharmacology, 11(3): 315-335. https:// doi.org/10.2174/1570159X11311030006
  • Corbett A, Pickett J, Burns A, Corcoran J, Dunnett SB et al. 2012. Drug repositioning for Alzheimer’s disease. Nature Reviews Drug Discovery, 11(11): 833-846. https://doi:10.1038/nrd3869
  • Deardorff WJ, Grossberg GT 2019. Behavioral and psychological symptoms in Alzheimer’s dementia and vascular dementia. In Handbook of Clinical Neurology (1st ed., Vol. 165). Elsevier B.V. 165: 5-32 https://doi.org/10.1016/B978-0-444-64012-3.00002-2.
  • Essmann U, Perera L, Berkowitz ML, Darden T, Lee H et al. 1995. A smooth particle mesh Ewald method. The Journal of Chemical Physics, 103(19): 8577-8593. https://doi.org/10.1063/1.470117
  • Gaussian 09, Revision E.01, Frisch M. J., Trucks G. W., Schlegel H. B., Scuseria G. E., Robb M. A., Cheeseman J. R., Scalmani G., Barone V., Mennucci B., Petersson G. A., et. al. Gaussian, Inc., Wallingford CT, 2009.
  • Gauthier S, Rosa-Neto P, Morais JA, Webster C 2021. World Alzheimer Report 2021: Journey through the diagnosis of dementia. London, England: Alzheimer’s Disease International.
  • Giacobini E 2003. Cholinesterases: new roles in brain function and in Alzheimer’s disease. Neurochemical Research, 28(3): 515–522. https://doi.org/10.1023/A:1022869222652
  • Greig NH, Lahiri DK, Sambamurti K 2002. Butyrylcholinesterase: an important new target in Alzheimer’s disease therapy. International Psychogeriatrics, 14: 77-91. https://doi.org/ 10.1017/S1041610203008676
  • Jellinger, KA 2010. Basic mechanisms of neurodegeneration: a critical update. Journal of Cellular and Molecular Medicine, 14(3): 457-487. https://doi.org/10.1111/j.1582-4934.2010.01010.x
  • Kim JH, Thao NP, Han YK, Lee YS, Luyen BT T et al. 2018. The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim. Journal of Enzyme Inhibition and Medicinal Chemistry, 33(1): 1174-1180. https://doi.org/10.1080/ 14756366.2018.1491847
  • Luque-Contreras D, Carvajal K, Toral-Rios D, Franco-Bocanegra D, Campos-Peña V 2014. Oxidative stress and metabolic syndrome: cause or consequence of Alzheimer’s disease? Oxidative Medicine and Cellular Longevity, 2014: 497802. https://doi.org/10.1155/2014/497802.
  • Mendez MF 2012. Early-onset Alzheimer’s disease: nonamnestic subtypes and type 2 AD. Archives of Medical Research, 43(8): 677-685. https://doi.org/ 10.1016/j.arcmed.2012.11.009
  • Mendiola-Precoma J, Rodríguez-Cruz A, García-Alcocer G 2016. The Etiology of Alzheimer’s Disease. 1–14. https://doi.org/10.1155/ 2016/2589276
  • Ravindranath PA, Forli S, Goodsell DS, Olson AJ, Sanner MF 2015. AutoDockFR: advances in protein-ligand docking with explicitly specified binding site flexibility. PLoS Computational Biology, 11(12): e1004586. https://doi.org/10.1371/ journal.pcbi.1004586
  • Revett TJ, Baker GB, Jhamandas J, Kar S 2013. Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology. Journal of Psychiatry and Neuroscience, 38(1): 6-23. doi: 10.1503/jpn.110190
  • Trott O, Olson AJ 2010. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 31(2): 455-461.
  • Van Cauwenberghe C, Van Broeckhoven C, Sleegers K 2016. The genetic landscape of Alzheimer disease: clinical implications and perspectives. Genetics in Medicine, 18(5): 421-430. https://doi.org/10.1038/gim.2015.117
  • Vos T, Allen C, Arora M, Barber RM, Bhutta ZA et al. 2016. Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. The Lancet, 388(10053): 1545-1602. https://doi.org/10.1016/S0140-6736(16)31678-6
  • Wittenauer BR, Smith L 2013. Priority Medicines for Europe and the World " A Public Health Approach to Innovation " Update on 2004 Background Paper. Who, December.
  • Zhao QF, Tan L, Wang HF, Jiang T, Tan MS et al. 2016. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: systematic review and meta-analysis. Journal of Affective Disorders, 190: 264-271. https://doi.org/10.1016/ j.jad.2015.09.069
There are 25 citations in total.

Details

Primary Language English
Subjects Structural Biology
Journal Section RESEARCH ARTICLE
Authors

Zaid Jaafar Awad Al-nuaimi 0000-0003-4585-2488

Abuzer Çelekli 0000-0002-2448-4957

Tugba Taskın Tok 0000-0002-0064-8400

Publication Date December 30, 2022
Submission Date March 23, 2022
Acceptance Date May 9, 2022
Published in Issue Year 2022Volume: 25 Issue: Ek Sayı 2

Cite

APA Al-nuaimi, Z. J. A., Çelekli, A., & Taskın Tok, T. (2022). Computational Approaches for Drug Repurposing in Alzheimer’s Disease. Kahramanmaraş Sütçü İmam Üniversitesi Tarım Ve Doğa Dergisi, 25(Ek Sayı 2), 307-315. https://doi.org/10.18016/ksutarimdoga.vi.1092038
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