Reports of Biochemistry
and Molecular Biology
Thu, Nov 21, 2024
[Archive]
Volume 12, Issue 2 (Vol.12 No.2 Jul 2023)
rbmb.net 2023, 12(2): 340-349 |
Back to browse issues page
Download citation:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
BibTeX | RIS | EndNote | Medlars | ProCite | Reference Manager | RefWorks
Send citation to:
Trasviña-Arenas C H, Ayala Medina L A, Vique-Sanchez J L. γ-Secretase Inhibitors Selected by Molecular Docking, to Develop a New Drug Against Alzheimer's Disease. rbmb.net 2023; 12 (2) :340-349
URL: http://rbmb.net/article-1-1218-en.html
URL: http://rbmb.net/article-1-1218-en.html
Research Center on Aging, Center for Research and Advanced Studies of the National Polytechnic Institute (CINVESTAV), Calzada de los Tenorios No. 235, 14330, Mexico City, Mexico.
Abstract: (1157 Views)
Background: Alzheimer´s disease (AD) is one of the most common forms of dementia, is characterized by memory loss and cognitive impairment that affects more than 30 million people worldwide. The pathogenesis of Alzheimer's disease is primary driven by brain accumulation of the amyloid β peptide generated from the amyloid-β precursor protein (APP) via cleavages by β- and γ-secretase. In this study, we propose an approach by molecular docking to select compounds as γ-secretase inhibitors for decreasing the APP generation.
Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds.
Results: Eight compounds (AZ1 – AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation.
Conclusion: AZ1 – AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.
Methods: We selected potential γ-secretase inhibitors by molecular docking in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in presenilin-1 (PS-1), using a chemical library of over 500,000 compounds.
Results: Eight compounds (AZ1 – AZ8) were selected by molecular docking to develop γ-secretase inhibitors for decreasing the APP generation.
Conclusion: AZ1 – AZ8 compounds could be interacting in the potential site between Asp257, Lue268, Asp385, Ile387, Phe388, and Leu432 amino acids in PS-1. These compounds could specifically interact in the binding pocket in PS-1 to prevent/decrease the APP generation, to develop a new drug against Alzheimer's disease.
Keywords: Amyloid Beta-Protein Precursor, Amyloid Precursor Protein Secretases, Alzheimer’s disease, Molecular Docking Simulation, Presenilin-1.
Type of Article: Original Article |
Subject:
Molecular Biology
Received: 2023/08/9 | Accepted: 2023/09/15 | Published: 2023/12/20
Received: 2023/08/9 | Accepted: 2023/09/15 | Published: 2023/12/20
References
1. Wolfe MS. Probing Mechanisms and Therapeutic Potential of γ-Secretase in Alzheimer's Disease. Molecules. 2021;26(2):388. [DOI:10.3390/molecules26020388] [PMID] []
2. Alzheimer's Disease International (2023). Alzheimer's disease international. https://www.alzint.org/about/dementia-facts-figures/dementia-statistics/.
3. Xu Y, Wang C, Wey H-Y, Liang Y, Chen Z, Choi SH, et al. Molecular imaging of Alzheimer's disease-related gamma-secretase in mice and nonhuman primates. J Exp Med. 2020;217(12):e20182266. [DOI:10.1084/jem.20182266] [PMID] []
4. Fukumori A, Feilen LP, Steiner H. Substrate recruitment by γ-secretase. Semin Cell Dev Biol. 2020;105:54-63. [DOI:10.1016/j.semcdb.2020.03.006] [PMID]
5. Boldin R, Zychar BC, Gonçalves LRC, Sciani JM. Design, in silico and pharmacological evaluation of a peptide inhibitor of BACE-1. Front Pharmacol. 2023;14:1184006. [DOI:10.3389/fphar.2023.1184006] [PMID] []
6. Wakabayashi T, De Strooper B. Presenilins: Members of the γ-Secretase Quartets, But Part-Time Soloists Too. Physiology. 2008;23(4):194-204. [DOI:10.1152/physiol.00009.2008] [PMID]
7. Yaghoobi H, Azizi H, Banitalebi-Dehkordi M, Mohammad Rezaei F, Arsang-Jnag S, Taheri M, et al. Beta-Secretase 1 (BACE1) Is Down-Regulated in Invasive Ductal Carcinoma of Breast. Reports Biochem Mol Biol. 2019;8(2):200-7.
8. Hardy J, Selkoe DJ. The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. Science. 2002;297(5580):353-6. [DOI:10.1126/science.1072994] [PMID]
9. Chan HH, Leong YQ, Voon SM, Pan ML, Leong CO, Lim CL, et al. Effects of Amyloid Precursor Protein Overexpression on NF-κB, Rho-GTPase and Pro-Apoptosis Bcl-2 Pathways in Neuronal Cells. Reports Biochem Mol Biol. 2021;9(4):417-25. [DOI:10.52547/rbmb.9.4.417] [PMID] []
10. Soria Lopez JA, Gonzalez HM, and Leger GC. Chapter 13 - Alzheimer's disease. Handbook of Clinical Neurology 2019; 167: 231-255. [DOI:10.1016/B978-0-12-804766-8.00013-3] [PMID]
11. Wolfe MS. Unraveling the complexity of γ-secretase. Semin Cell Dev Biol. 2020;105:3-11. [DOI:10.1016/j.semcdb.2020.01.005] [PMID] []
12. De Strooper B. Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex. Neuron. 2003;38(1):9-12. [DOI:10.1016/S0896-6273(03)00205-8] [PMID]
13. Kaether C, Haass C, Steiner H. Assembly, trafficking and function of gamma-secretase. Neurodegener Dis. 2006;3(4-5):275-83. [DOI:10.1159/000095267] [PMID]
14. Yang G, Zhou R, Guo X, Yan C, Lei J, Shi Y. Structural basis of γ-secretase inhibition and modulation by small molecule drugs. Cell. 2021;184(2):521-533.e14. [DOI:10.1016/j.cell.2020.11.049] [PMID]
15. Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, et al. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis. 2020;139:104817. [DOI:10.1016/j.nbd.2020.104817] [PMID] []
16. Escamilla-Ayala A, Wouters R, Sannerud R, Annaert W. Contribution of the Presenilins in the cell biology, structure and function of γ-secretase. Semin Cell Dev Biol. 2020;105:12-26. [DOI:10.1016/j.semcdb.2020.02.005] [PMID]
17. Giau VV, Bagyinszky E, Youn YC, An SSA, Kim S. APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease. Int J Mol Sci. 2019;20(19):4757. [DOI:10.3390/ijms20194757] [PMID] []
18. Martikainen P, Pikkarainen M, Pöntynen K, Hiltunen M, Lehtovirta M, Tuisku S, et al. Brain pathology in three subjects from the same pedigree with presenilin-1 ( PSEN1 ) P264L mutation. Neuropathol Appl Neurobiol. 2010;36(1):41-54. [DOI:10.1111/j.1365-2990.2009.01046.x] [PMID]
19. Acosta-Baena N, Sepulveda-Falla D, Lopera-Gómez CM, Jaramillo-Elorza MC, Moreno S, Aguirre-Acevedo DC, et al. Pre-dementia clinical stages in presenilin 1 E280A familial early-onset Alzheimer's disease: a retrospective cohort study. Lancet Neurol. 2011;10(3):213-20. [DOI:10.1016/S1474-4422(10)70323-9] [PMID]
20. Shen L, Qin W, Wu L, Zhou A, Tang Y, Wang Q, et al. Two novel presenilin-1 mutations (I249L and P433S) in early onset Chinese Alzheimer's pedigrees and their functional characterization. Biochem Biophys Res Commun. 2019;516(1):264-9. [DOI:10.1016/j.bbrc.2019.05.185] [PMID]
21. PSEN1 presenilin 1 [ Homo sapiens (human) ] NCBI. 2023. https://www.ncbi.nlm.nih.gov/gene/5663.
22. Yi P, Hadden C, Kulanthaivel P, Calvert N, Annes W, Brown T, et al. Disposition and metabolism of semagacestat, a {gamma}-secretase inhibitor, in humans. Drug Metab Dispos. 2010;38(4):554-65. [DOI:10.1124/dmd.109.030841] [PMID]
23. Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, et al. Structural basis of Notch recognition by human γ-secretase. Nature. 2019;565(7738):192-7.
https://doi.org/10.1038/d41586-019-01455-5 [DOI:10.1038/s41586-018-0813-8]
24. Sun Y, Xu L, Zheng D, Wang J, Liu G, Mo Z, et al. A potent phosphodiester Keap1-Nrf2 protein-protein interaction inhibitor as the efficient treatment of Alzheimer's disease. Redox Biol. 2023;64:102793. [DOI:10.1016/j.redox.2023.102793] [PMID] []
25. Passero M, Zhai T, Huang Z. Investigation of Potential Drug Targets for Cholesterol Regulation to Treat Alzheimer's Disease. Int J Environ Res Public Health. 2023;20(13):6217. [DOI:10.3390/ijerph20136217] [PMID] []
26. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019;363(6428):eaaw0930. [DOI:10.1126/science.aaw0930] [PMID]
27. RCSB, Protein Data Bank. https://www.rcsb.org.
28. Brooks BR, Brooks CL, Mackerell AD, Nilsson L, Petrella RJ, Roux B, et al. CHARMM: The biomolecular simulation program. J Comput Chem. 2009;30(10):1545-614. [DOI:10.1002/jcc.21287] [PMID] []
29. ChemBridge Corp. [Internet]. EXPRESS-Pick Stock. 2021. https://chembridge.com/screening_libraries/#EXPRESSPick.
30. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26. [DOI:10.1016/S0169-409X(96)00423-1]
31. Thangapandian S, John S, Lee Y, Kim S, Lee KW. Dynamic Structure-Based Pharmacophore Model Development: A New and Effective Addition in the Histone Deacetylase 8 (HDAC8) Inhibitor Discovery. Int J Mol Sci. 2011;12(12):9440-62. [DOI:10.3390/ijms12129440] [PMID] []
32. Vique-Sánchez JL. Potential inhibitors interacting in Neuropilin-1 to develop an adjuvant drug against COVID-19, by molecular docking. Bioorg Med Chem. 2021;33:116040. [DOI:10.1016/j.bmc.2021.116040] [PMID] []
33. Muegge I. Selection criteria for drug-like compounds. Med Res Rev. 2003;23(3):302-21. [DOI:10.1002/med.10041] [PMID]
34. Adasme MF, Linnemann KL, Bolz SN, Kaiser F, Salentin S, Haupt VJ, et al. PLIP 2021: expanding the scope of the protein-ligand interaction profiler to DNA and RNA. Nucleic Acids Res. 2021;49(W1):W530-4. [DOI:10.1093/nar/gkab294] [PMID] []
35. Galindo-Hernández O, García-Salazar LA, García-González VG, Díaz-Molina R, Vique-Sánchez JL. Potential Inhibitors of The OTUB1 Catalytic Site to Develop an Anti-Cancer Drug Using In-Silico Approaches. Reports Biochem Mol Biol. 2023;11(4):684-93. [DOI:10.52547/rbmb.11.4.684] [PMID] []
36. www.acdlabs.com/. https://www.acdlabs.com/products/percepta/index.php
37. Dong J, Wang N-N, Yao Z-J, Zhang L, Cheng Y, Ouyang D, et al. ADMETlab: a platform for systematic ADMET evaluation based on a comprehensively collected ADMET database. J Cheminform. 2018;10(1):29. [DOI:10.1186/s13321-018-0283-x] [PMID] []
38. Banerjee P, Eckert AO, Schrey AK, Preissner R. ProTox-II: a webserver for the prediction of toxicity of chemicals. Nucleic Acids Res. 2018;46(W1):W257-63. [DOI:10.1093/nar/gky318] [PMID] []
39. Sato C, Takagi S, Tomita T, Iwatsubo T. The C-Terminal PAL Motif and Transmembrane Domain 9 of Presenilin 1 Are Involved in the Formation of the Catalytic Pore of the -Secretase. J Neurosci. 2008;28(24):6264-71. [DOI:10.1523/JNEUROSCI.1163-08.2008] [PMID] []
| Rights and permissions | |
 |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
