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In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer's Drug Development

Yıl 2025, Cilt: 8 Sayı: 3, 715 - 728, 15.05.2025

Barış Kurt , Murat Evcil , Ayşe Baran

https://doi.org/10.34248/bsengineering.1640219

Öz

Alzheimer's disease is a long-term neurological disorder that affects memory and other cognitive abilities. Physostigmine is a drug still used in treating symptoms associated with this disease, with its primary mechanism of action being AChE inhibition. AChE plays a crucial role in cholinergic neurotransmission, and its inhibition has been linked to the improvement of symptoms in Alzheimer's disease. In this study, 34 phytochemicals detected through LC-MS/MS analysis of 13 plant species were investigated as potential alternative drug candidates to physostigmine. For this purpose, docking studies followed by molecular dynamics simulations and MM/GBSA energy calculations were performed. The results revealed that 24 out of 34 phytochemicals were either very close to physostigmine (MM/GBSA binding affinity: -26.102 kcal/mol) or better AChE inhibitors. Additionally, it was determined that physostigmine increased the flexibility of the molecule when bound to the AChE enzyme, a unique result compared to our drug candidates. Our research emphasizes the potential of plant-derived compounds as AChE inhibitors and presents promising candidates for future drug development studies. Furthermore, physostigmine's property of increasing enzyme flexibility offers a new perspective in drug design and indicates that the role of this feature in therapeutic efficacy needs to be examined in more detail.

Anahtar Kelimeler

Medicinal plants MM/GBSA In silico Drug development

Kaynakça

  • Baran MF, Keskin C, Baran A, Eftekhari A, Omarova S, Khalilov R, Atalar MN. 2023. The investigation of the chemical composition and applicability of gold nanoparticles synthesized with Amygdalus communis (almond) leaf aqueous extract as antimicrobial and anticancer agents. Molecules, 28(6): 2428. https://doi.org/10.3390/molecules28062428
  • Benfante R, Di Lascio S, Cardani S, Fornasari D. 2021. Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders. Aging Clin Exp Res, 33(4): 823-834. https://doi.org/10.1007/s40520-019-01359-4
  • Berman HM. 2000. The protein data bank. Nucleic Acids Res, 28(1): 235-242. https://doi.org/10.1093/nar/28.1.235.
  • BIOVIA, 2019. Discovery studio visualizer. Dassault Systèmes, San Diego, CA, USA, pp:152.
  • Bortolami M, Rocco D, Messore A, Di Santo R, Costi R, Madia VN, Pandolfi F. 2021. Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease - a patent review (2016-present). Expert Opin Ther Pat, 31(5): 399-420. https://doi.org/10.1080/13543776.2021.1874344
  • Case DA, Aktulga HM, Belfon K, Ben-Shalom IY, Berryman JT, Brozell SR, Xiong Y. 2023. AMBER 2023. University of California, San Francisco, CA, USA, pp: 32.
  • Coelho Filho JM, Birks J. 2001. Physostigmine for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev, 2001(2): CD001499. https://doi.org/10.1002/14651858.CD001499
  • Dorronsoro I, Castro A, Martinez A. 2003. Peripheral and dual binding site inhibitors of acetylcholinesterase as neurodegenerative disease modifying agents. Expert Opin Ther Pat, 13(11): 1725-1732. https://doi.org/10.1517/13543776.13.11.1725
  • Eastman P, Swails J, Chodera JD, McGibbon RT, Zhao Y, Beauchamp KA, Pande VS. 2017. OpenMM 7: rapid development of high performance algorithms for molecular dynamics. PLoS Comput Biol, 13(7): e1005659. https://doi.org/10.1371/journal.pcbi.1005659
  • Eberhardt J, Santos-Martins D, Tillack AF, Forli S. 2021. AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python bindings. J Chem Inf Model, 61(8): 3891-3898. https://doi.org/10.1021/acs.jcim.1c00203
  • Groom CR, Bruno IJ, Lightfoot MP, Ward SC. 2016. The Cambridge structural database. Acta Crystallogr B, 72(2): 171-179. https://doi.org/10.1107/S2052520616003954
  • Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, Khachaturian ZS. 2018. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 141(7): 1917-1933. https://doi.org/10.1093/brain/awy132
  • Hopkins CW, Le Grand S, Walker RC, Roitberg AE. 2015. Long-time-step molecular dynamics through hydrogen mass repartitioning. J Chem Theory Comput, 11(4): 1864-1874. https://doi.org/10.1021/ct5010406
  • Howes MR, Perry NSL, Houghton PJ. 2003. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res, 17(1): 1-18. https://doi.org/10.1002/ptr.1280
  • Huang L, Su T, Li X. 2013. Natural products as sources of new lead compounds for the treatment of Alzheimer’s disease. Curr Top Med Chem, 13(15): 1864-1878. https://doi.org/10.2174/15680266113139990142
  • Jenike MA, Albert M, Baer L, Gunther J. 1990. Oral physostigmine as treatment for primary degenerative dementia: a double-blind placebo-controlled inpatient trial. J Geriatr Psychiatry Neurol, 3(1): 13-16. https://doi.org/10.1177/089198879000300104
  • Kabir MT, Uddin MS, Begum MM, Thangapandiyan S, Rahman MS, Aleya L, Ashraf GM. 2019. Cholinesterase inhibitors for Alzheimer’s disease: multitargeting strategy based on anti-Alzheimer’s drugs repositioning. Curr Pharm Des, 25(33): 3519-3535. https://doi.org/10.2174/1381612825666191008103141
  • Kurt B. 2022. Investigation of the potential inhibitor effects of lycorine on SARS-CoV-2 main protease (Mpro) using molecular dynamics simulations and MMPBSA. Int J Life Sci Biotechnol, 5(3): 424-435. https://doi.org/10.38001/ijlsb.1110761
  • Kurt B, Temel H, Atlan M, Kaya S. 2020. Synthesis, characterization, DNA interaction and docking studies of novel Schiff base ligand derived from 2,6-diaminopyridine and its complexes. J Mol Struct, 1209: 127928. https://doi.org/10.1016/j.molstruc.2020.127928
  • Lustoza Rodrigues TCM, de Sousa NF, dos Santos AMF, Aires Guimarães RD, Scotti MT, Scotti L. 2023. Challenges and discoveries in polypharmacology of neurodegenerative diseases. Curr Top Med Chem, 23(5): 349-370. https://doi.org/10.2174/1568026623666230126112628
  • Mantegazza R, Vanoli F, Frangiamore R, Cavalcante P. 2020. Complement inhibition for the treatment of myasthenia gravis. Immunotargets Ther, 9: 317-331. https://doi.org/10.2147/ITT.S261414
  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem, 30(16): 2785-2791. https://doi.org/10.1002/jcc.21256
  • Mukherjee PK, Kumar V, Mal M, Houghton PJ. 2007. Acetylcholinesterase inhibitors from plants. Phytomedicine, 14(4): 289-300. https://doi.org/10.1016/j.phymed.2007.02.002
  • Murray A, Faraoni M, Castro M, Alza N, Cavallaro V. 2013. Natural AChE inhibitors from plants and their contribution to Alzheimer’s disease therapy. Curr Neuropharmacol, 11(4): 388-413. https://doi.org/10.2174/1570159X11311040004
  • Pence HE, Williams A. 2010. ChemSpider: an online chemical information resource. J Chem Educ, 87(11): 1123-1124. https://doi.org/10.1021/ed100697w
  • Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. 2004. UCSF Chimera: a visualization system for exploratory research and analysis. J Comput Chem, 25(13): 1605-1612. https://doi.org/10.1002/jcc.20084
  • Punga AR, Stålberg E. 2009. Acetylcholinesterase inhibitors in MG: to be or not to be? Muscle Nerve, 39(6): 724-728. https://doi.org/10.1002/mus.21319
  • Ranjan N, Kumari M. 2017. Acetylcholinesterase inhibition by medicinal plants: a review. Ann Plant Sci, 6(6): 1640. https://doi.org/10.21746/aps.2017.06.003
  • Reale M, Costantini E. 2021. Cholinergic modulation of the immune system in neuroinflammatory diseases. Diseases, 9(2): 29. https://doi.org/10.3390/diseases9020029
  • Thal LJ, Fuld PA, Masur DM, Sharpless NS. 1983. Oral physostigmine and lecithin improve memory in Alzheimer disease. Ann Neurol, 13(5): 491-496. https://doi.org/10.1002/ana.410130504
  • Walczak-Nowicka ŁJ, Herbet M. 2021. Acetylcholinesterase inhibitors in the treatment of neurodegenerative diseases and the role of acetylcholinesterase in their pathogenesis. Int J Mol Sci, 22(17): 9290. https://doi.org/10.3390/ijms22179290
  • Zimmerman G, Soreq H. 2006. Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission. Cell Tissue Res, 326(2): 655-669. https://doi.org/10.1007/s00441-006-0239-8

In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer's Drug Development

Yıl 2025, Cilt: 8 Sayı: 3, 715 - 728, 15.05.2025

Barış Kurt , Murat Evcil , Ayşe Baran

https://doi.org/10.34248/bsengineering.1640219

Öz

Alzheimer's disease is a long-term neurological disorder that affects memory and other cognitive abilities. Physostigmine is a drug still used in treating symptoms associated with this disease, with its primary mechanism of action being AChE inhibition. AChE plays a crucial role in cholinergic neurotransmission, and its inhibition has been linked to the improvement of symptoms in Alzheimer's disease. In this study, 34 phytochemicals detected through LC-MS/MS analysis of 13 plant species were investigated as potential alternative drug candidates to physostigmine. For this purpose, docking studies followed by molecular dynamics simulations and MM/GBSA energy calculations were performed. The results revealed that 24 out of 34 phytochemicals were either very close to physostigmine (MM/GBSA binding affinity: -26.102 kcal/mol) or better AChE inhibitors. Additionally, it was determined that physostigmine increased the flexibility of the molecule when bound to the AChE enzyme, a unique result compared to our drug candidates. Our research emphasizes the potential of plant-derived compounds as AChE inhibitors and presents promising candidates for future drug development studies. Furthermore, physostigmine's property of increasing enzyme flexibility offers a new perspective in drug design and indicates that the role of this feature in therapeutic efficacy needs to be examined in more detail.

Anahtar Kelimeler

Medicinal plants MM/GBSA In silico Drug development

Kaynakça

  • Baran MF, Keskin C, Baran A, Eftekhari A, Omarova S, Khalilov R, Atalar MN. 2023. The investigation of the chemical composition and applicability of gold nanoparticles synthesized with Amygdalus communis (almond) leaf aqueous extract as antimicrobial and anticancer agents. Molecules, 28(6): 2428. https://doi.org/10.3390/molecules28062428
  • Benfante R, Di Lascio S, Cardani S, Fornasari D. 2021. Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders. Aging Clin Exp Res, 33(4): 823-834. https://doi.org/10.1007/s40520-019-01359-4
  • Berman HM. 2000. The protein data bank. Nucleic Acids Res, 28(1): 235-242. https://doi.org/10.1093/nar/28.1.235.
  • BIOVIA, 2019. Discovery studio visualizer. Dassault Systèmes, San Diego, CA, USA, pp:152.
  • Bortolami M, Rocco D, Messore A, Di Santo R, Costi R, Madia VN, Pandolfi F. 2021. Acetylcholinesterase inhibitors for the treatment of Alzheimer’s disease - a patent review (2016-present). Expert Opin Ther Pat, 31(5): 399-420. https://doi.org/10.1080/13543776.2021.1874344
  • Case DA, Aktulga HM, Belfon K, Ben-Shalom IY, Berryman JT, Brozell SR, Xiong Y. 2023. AMBER 2023. University of California, San Francisco, CA, USA, pp: 32.
  • Coelho Filho JM, Birks J. 2001. Physostigmine for dementia due to Alzheimer’s disease. Cochrane Database Syst Rev, 2001(2): CD001499. https://doi.org/10.1002/14651858.CD001499
  • Dorronsoro I, Castro A, Martinez A. 2003. Peripheral and dual binding site inhibitors of acetylcholinesterase as neurodegenerative disease modifying agents. Expert Opin Ther Pat, 13(11): 1725-1732. https://doi.org/10.1517/13543776.13.11.1725
  • Eastman P, Swails J, Chodera JD, McGibbon RT, Zhao Y, Beauchamp KA, Pande VS. 2017. OpenMM 7: rapid development of high performance algorithms for molecular dynamics. PLoS Comput Biol, 13(7): e1005659. https://doi.org/10.1371/journal.pcbi.1005659
  • Eberhardt J, Santos-Martins D, Tillack AF, Forli S. 2021. AutoDock Vina 1.2.0: new docking methods, expanded force field, and Python bindings. J Chem Inf Model, 61(8): 3891-3898. https://doi.org/10.1021/acs.jcim.1c00203
  • Groom CR, Bruno IJ, Lightfoot MP, Ward SC. 2016. The Cambridge structural database. Acta Crystallogr B, 72(2): 171-179. https://doi.org/10.1107/S2052520616003954
  • Hampel H, Mesulam MM, Cuello AC, Farlow MR, Giacobini E, Grossberg GT, Khachaturian ZS. 2018. The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease. Brain, 141(7): 1917-1933. https://doi.org/10.1093/brain/awy132
  • Hopkins CW, Le Grand S, Walker RC, Roitberg AE. 2015. Long-time-step molecular dynamics through hydrogen mass repartitioning. J Chem Theory Comput, 11(4): 1864-1874. https://doi.org/10.1021/ct5010406
  • Howes MR, Perry NSL, Houghton PJ. 2003. Plants with traditional uses and activities, relevant to the management of Alzheimer’s disease and other cognitive disorders. Phytother Res, 17(1): 1-18. https://doi.org/10.1002/ptr.1280
  • Huang L, Su T, Li X. 2013. Natural products as sources of new lead compounds for the treatment of Alzheimer’s disease. Curr Top Med Chem, 13(15): 1864-1878. https://doi.org/10.2174/15680266113139990142
  • Jenike MA, Albert M, Baer L, Gunther J. 1990. Oral physostigmine as treatment for primary degenerative dementia: a double-blind placebo-controlled inpatient trial. J Geriatr Psychiatry Neurol, 3(1): 13-16. https://doi.org/10.1177/089198879000300104
  • Kabir MT, Uddin MS, Begum MM, Thangapandiyan S, Rahman MS, Aleya L, Ashraf GM. 2019. Cholinesterase inhibitors for Alzheimer’s disease: multitargeting strategy based on anti-Alzheimer’s drugs repositioning. Curr Pharm Des, 25(33): 3519-3535. https://doi.org/10.2174/1381612825666191008103141
  • Kurt B. 2022. Investigation of the potential inhibitor effects of lycorine on SARS-CoV-2 main protease (Mpro) using molecular dynamics simulations and MMPBSA. Int J Life Sci Biotechnol, 5(3): 424-435. https://doi.org/10.38001/ijlsb.1110761
  • Kurt B, Temel H, Atlan M, Kaya S. 2020. Synthesis, characterization, DNA interaction and docking studies of novel Schiff base ligand derived from 2,6-diaminopyridine and its complexes. J Mol Struct, 1209: 127928. https://doi.org/10.1016/j.molstruc.2020.127928
  • Lustoza Rodrigues TCM, de Sousa NF, dos Santos AMF, Aires Guimarães RD, Scotti MT, Scotti L. 2023. Challenges and discoveries in polypharmacology of neurodegenerative diseases. Curr Top Med Chem, 23(5): 349-370. https://doi.org/10.2174/1568026623666230126112628
  • Mantegazza R, Vanoli F, Frangiamore R, Cavalcante P. 2020. Complement inhibition for the treatment of myasthenia gravis. Immunotargets Ther, 9: 317-331. https://doi.org/10.2147/ITT.S261414
  • Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ. 2009. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem, 30(16): 2785-2791. https://doi.org/10.1002/jcc.21256
  • Mukherjee PK, Kumar V, Mal M, Houghton PJ. 2007. Acetylcholinesterase inhibitors from plants. Phytomedicine, 14(4): 289-300. https://doi.org/10.1016/j.phymed.2007.02.002
  • Murray A, Faraoni M, Castro M, Alza N, Cavallaro V. 2013. Natural AChE inhibitors from plants and their contribution to Alzheimer’s disease therapy. Curr Neuropharmacol, 11(4): 388-413. https://doi.org/10.2174/1570159X11311040004
  • Pence HE, Williams A. 2010. ChemSpider: an online chemical information resource. J Chem Educ, 87(11): 1123-1124. https://doi.org/10.1021/ed100697w
  • Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE. 2004. UCSF Chimera: a visualization system for exploratory research and analysis. J Comput Chem, 25(13): 1605-1612. https://doi.org/10.1002/jcc.20084
  • Punga AR, Stålberg E. 2009. Acetylcholinesterase inhibitors in MG: to be or not to be? Muscle Nerve, 39(6): 724-728. https://doi.org/10.1002/mus.21319
  • Ranjan N, Kumari M. 2017. Acetylcholinesterase inhibition by medicinal plants: a review. Ann Plant Sci, 6(6): 1640. https://doi.org/10.21746/aps.2017.06.003
  • Reale M, Costantini E. 2021. Cholinergic modulation of the immune system in neuroinflammatory diseases. Diseases, 9(2): 29. https://doi.org/10.3390/diseases9020029
  • Thal LJ, Fuld PA, Masur DM, Sharpless NS. 1983. Oral physostigmine and lecithin improve memory in Alzheimer disease. Ann Neurol, 13(5): 491-496. https://doi.org/10.1002/ana.410130504
  • Walczak-Nowicka ŁJ, Herbet M. 2021. Acetylcholinesterase inhibitors in the treatment of neurodegenerative diseases and the role of acetylcholinesterase in their pathogenesis. Int J Mol Sci, 22(17): 9290. https://doi.org/10.3390/ijms22179290
  • Zimmerman G, Soreq H. 2006. Termination and beyond: acetylcholinesterase as a modulator of synaptic transmission. Cell Tissue Res, 326(2): 655-669. https://doi.org/10.1007/s00441-006-0239-8
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Moleküler İlaç
Bölüm Research Articles
Yazarlar

Barış Kurt 0000-0002-1406-0915

Murat Evcil 0000-0002-4646-8042

Ayşe Baran 0000-0002-2317-0489

Yayımlanma Tarihi 15 Mayıs 2025
Gönderilme Tarihi 14 Şubat 2025
Kabul Tarihi 21 Mart 2025
Yayımlandığı Sayı Yıl 2025 Cilt: 8 Sayı: 3

Kaynak Göster

APA Kurt, B., Evcil, M., & Baran, A. (2025). In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development. Black Sea Journal of Engineering and Science, 8(3), 715-728. https://doi.org/10.34248/bsengineering.1640219
AMA Kurt B, Evcil M, Baran A. In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development. BSJ Eng. Sci. Mayıs 2025;8(3):715-728. doi:10.34248/bsengineering.1640219
Chicago Kurt, Barış, Murat Evcil, ve Ayşe Baran. “In Silico Exploration of Plant Extracts As Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development”. Black Sea Journal of Engineering and Science 8, sy. 3 (Mayıs 2025): 715-28. https://doi.org/10.34248/bsengineering.1640219.
EndNote Kurt B, Evcil M, Baran A (01 Mayıs 2025) In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development. Black Sea Journal of Engineering and Science 8 3 715–728.
IEEE B. Kurt, M. Evcil, ve A. Baran, “In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development”, BSJ Eng. Sci., c. 8, sy. 3, ss. 715–728, 2025, doi: 10.34248/bsengineering.1640219.
ISNAD Kurt, Barış vd. “In Silico Exploration of Plant Extracts As Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development”. Black Sea Journal of Engineering and Science 8/3 (Mayıs 2025), 715-728. https://doi.org/10.34248/bsengineering.1640219.
JAMA Kurt B, Evcil M, Baran A. In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development. BSJ Eng. Sci. 2025;8:715–728.
MLA Kurt, Barış vd. “In Silico Exploration of Plant Extracts As Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development”. Black Sea Journal of Engineering and Science, c. 8, sy. 3, 2025, ss. 715-28, doi:10.34248/bsengineering.1640219.
Vancouver Kurt B, Evcil M, Baran A. In Silico Exploration of Plant Extracts as Ache Inhibitors: Insights from Molecular Dynamics and Mm/Gbsa Analysis for Alzheimer’s Drug Development. BSJ Eng. Sci. 2025;8(3):715-28.
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