Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β


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Abstract

Background:Alzheimer's disease (AD) is one of the most concerned neurodegenerative disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies. In this study, we aimed to identify and establish promising dual inhibitors targeting BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively.

Methods:We have used molecular docking, ADME property analysis, and MMGBSA calculations for the identification of hit molecules and further evaluation of binding affinity, drug-like properties, and stability against BACE1 and GSK-3β.

Results:Our results demonstrated strong binding affinities of ZINC000034853956 towards the active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β. Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed in MD simulations support its suitability for further optimization and preclinical studies.

Conclusion:Further investigations are warranted to elucidate the precise molecular mechanisms and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.

About the authors

Magham Sai Varshini

Department of Pharmacology,, JSS Academy of Higher Education and Research

Email: info@benthamscience.net

Ramakkamma Aishwarya Reddy

Department of Pharmaceutics, JSS College of Pharmacy,, JSS Academy of Higher Education and Research,

Email: info@benthamscience.net

Praveen Thaggikuppe Krishnamurthy

Department of Pharmacology, JSS College of Pharmacy,, JSS Academy of Higher Education and Research,

Author for correspondence.
Email: info@benthamscience.net

Divakar Selvaraj

Department of Pharmacology, JSS College of Pharmacy,, JSS Academy of Higher Education and Research

Email: info@benthamscience.net

References

  1. Javaid, S.F.; Giebel, C.; Khan, M.A.B.; Hashim, M.J. Epidemiology of Alzheimer’s disease and other dementias: Rising global burden and forecasted trends. F1000 Res., 2021, 10, 425. doi: 10.12688/f1000research.50786.1
  2. Alzheimer’s disease facts and figures. Alzheimers Dement., 2022, 18(4), 700-789. doi: 10.1002/alz.12638 PMID: 35289055
  3. Dementia. Available from: https://www.who.int/news-room/fact-sheets/detail/dementia (cited 2023 Sep 4).
  4. Avila, J.; Hernández, F. GSK-3 inhibitors for Alzheimer’s disease. Expert Rev. Neurother., 2007, 7(11), 1527-1533. doi: 10.1586/14737175.7.11.1527 PMID: 17997701
  5. Tahami Monfared, A.A.; Byrnes, M.J.; White, L.A.; Zhang, Q. The humanistic and economic burden of alzheimer’s Disease. Neurol. Ther., 2022, 11(2), 525-551. doi: 10.1007/s40120-022-00335-x PMID: 35192176
  6. Zhu, C.W.; Sano, M. Economic considerations in the management of Alzheimer’s disease. Clin. Interv. Aging, 2006, 1(2), 143-154. doi: 10.2147/ciia.2006.1.2.143 PMID: 18044111
  7. Rampa, A.; Gobbi, S.; Concetta Di Martino, R.M.; Belluti, F.; Bisi, A. Dual BACE-1/GSK-3β inhibitors to combat alzheimer’s disease: A focused review. Curr. Top. Med. Chem., 2018, 17(31), 3361-3369. doi: 10.2174/1568026618666180112161406
  8. Goedert, M.; Spillantini, M.G. A century of Alzheimer’s disease. Science, 2006, 314(5800), 777-781. doi: 10.1126/science.1132814 PMID: 17082447
  9. Hernández, F.; Gómez de Barreda, E.; Fuster-Matanzo, A.; Lucas, J.J.; Avila, J. GSK3: A possible link between beta amyloid peptide and tau protein. Exp. Neurol., 2010, 223(2), 322-325. doi: 10.1016/j.expneurol.2009.09.011 PMID: 19782073
  10. Bloom, G.S. Amyloid-β and Tau. JAMA Neurol., 2014, 71(4), 505-508. doi: 10.1001/jamaneurol.2013.5847 PMID: 24493463
  11. Nisbet, R.M.; Götz, J. Amyloid-β and Tau in alzheimer’s disease: Novel pathomechanisms and non-pharmacological treatment strategies. J. Alzheimers Dis., 2018, 64(s1), S517-S527. doi: 10.3233/JAD-179907 PMID: 29562514
  12. Busche, M.A.; Hyman, B.T. Synergy between amyloid-β and tau in Alzheimer’s disease. Nat. Neurosci., 2020, 23(10), 1183-1193. doi: 10.1038/s41593-020-0687-6 PMID: 32778792
  13. Cavalli, A.; Bolognesi, M.L.; Minarini, A.; Rosini, M.; Tumiatti, V.; Recanatini, M.; Melchiorre, C. Multi-target-directed ligands to combat neurodegenerative diseases. J. Med. Chem., 2008, 51(3), 347-372. doi: 10.1021/jm7009364 PMID: 18181565
  14. Csermely, P.; Agoston, V.; Pongor, S. The efficiency of multi-target drugs: the network approach might help drug design. Trends Pharmacol. Sci., 2005, 26(4), 178-182. doi: 10.1016/j.tips.2005.02.007 PMID: 15808341
  15. Hughes, R.E.; Nikolic, K.; Ramsay, R.R. One for all? hitting multiple alzheimer’s disease targets with one drug. Front. Neurosci., 2016, 10, 177. doi: 10.3389/fnins.2016.00177 PMID: 27199640
  16. León, R.; Garcia, A.G.; Marco-Contelles, J. Recent advances in the multitarget-directed ligands approach for the treatment of Alzheimer’s disease. Med. Res. Rev., 2013, 33(1), 139-189. doi: 10.1002/med.20248 PMID: 21793014
  17. Teli, P.; Sahiba, N.; Soni, J.; Sethiya, A.; Agarwal, D.K.; Agarwal, S. Exploration of potent multi-target-directed-ligands as anti-alzheimer’s disease agents: A moiety based review. Mini Rev. Med. Chem., 2021, 21(20), 3219-3248. doi: 10.2174/1389557521666210304111754 PMID: 33663363
  18. Das, S.; Basu, S. Multi-targeting strategies for alzheimer’s disease therapeutics: Pros and Cons. Curr. Top. Med. Chem., 2017, 17(27), 3017-3061. PMID: 28685694
  19. Coimbra, J.R.M.; Marques, D.F.F.; Baptista, S.J.; Pereira, C.M.F.; Moreira, P.I.; Dinis, T.C.P.; Santos, A.E.; Salvador, J.A.R. Highlights in BACE1 Inhibitors for Alzheimer’s Disease Treatment. Front Chem., 2018, 6, 178. doi: 10.3389/fchem.2018.00178 PMID: 29881722
  20. Das, B.; Yan, R. A close look at BACE1 inhibitors for alzheimer’s disease treatment. CNS Drugs, 2019, 33(3), 251-263. doi: 10.1007/s40263-019-00613-7 PMID: 30830576
  21. Ghosh, A.K.; Osswald, H.L. BACE1 (β-secretase) inhibitors for the treatment of Alzheimer’s disease. Chem. Soc. Rev., 2014, 43(19), 6765-6813. doi: 10.1039/C3CS60460H PMID: 24691405
  22. Guo, T.; Hobbs, D. Development of BACE1 inhibitors for Alzheimer’s disease. Curr. Med. Chem., 2006, 13(15), 1811-1829. doi: 10.2174/092986706777452489 PMID: 16787223
  23. Hu, X.; Hicks, C.W.; He, W.; Wong, P.; Macklin, W.B.; Trapp, B.D.; Yan, R. Bace1 modulates myelination in the central and peripheral nervous system. Nat. Neurosci., 2006, 9(12), 1520-1525. doi: 10.1038/nn1797 PMID: 17099708
  24. Leroy, K.; Yilmaz, Z.; Brion, J.P. Increased level of active GSK-3? in Alzheimer’s disease and accumulation in argyrophilic grains and in neurones at different stages of neurofibrillary degeneration. Neuropathol. Appl. Neurobiol., 2007, 33(1), 43-55. doi: 10.1111/j.1365-2990.2006.00795.x PMID: 17239007
  25. Eldar-Finkelman, H.; Martinez, A. GSK-3 inhibitors: Preclinical and clinical focus on CNS. Front. Mol. Neurosci., 2011, 4, 32. doi: 10.3389/fnmol.2011.00032 PMID: 22065134
  26. Eldar-Finkelman, H.; Licht-Murava, A.; Pietrokovski, S.; Eisenstein, M. Substrate competitive GSK-3 inhibitors: Strategy and implications. Biochim. Biophys. Acta. Proteins Proteomics, 2010, 1804(3), 598-603. doi: 10.1016/j.bbapap.2009.09.010 PMID: 19770076
  27. Llorens-Martín, M.; Jurado, J.; Hernández, F.; Avila, J. GSK-3β, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci., 2014, 7, 46. doi: 10.3389/fnmol.2014.00046
  28. Doble, B.W.; Woodgett, J.R. GSK-3: Tricks of the trade for a multi-tasking kinase. J. Cell Sci., 2003, 116(7), 1175-1186. doi: 10.1242/jcs.00384 PMID: 12615961
  29. Kypta, R.M. GSK-3 inhibitors and their potential in the treatment of Alzheimer’s disease. Expert Opin. Ther. Pat., 2005, 15(10), 1315-1331. doi: 10.1517/13543776.15.10.1315
  30. Lei, P.; Ayton, S.; Bush, A.I.; Adlard, P.A. GSK-3 in neurodegenerative diseases. Int. J. Alzheimers Dis., 2011, 2011, 1-9. doi: 10.4061/2011/189246 PMID: 21629738
  31. Paudel, P.; Seong, S.H.; Zhou, Y.; Ha, M.T.; Min, B.S.; Jung, H.A.; Choi, J.S. Arylbenzofurans from the Root Bark of Morus alba as triple inhibitors of cholinesterase, β-site amyloid precursor protein cleaving enzyme 1, and glycogen synthase kinase-3β: Relevance to alzheimer’s disease. ACS Omega, 2019, 4(4), 6283-6294. doi: 10.1021/acsomega.9b00198 PMID: 31459768
  32. Jiang, X.; Lu, H.; Li, J.; Liu, W.; Wu, Q.; Xu, Z.; Qiao, Q.; Zhang, H.; Gao, H.; Zhao, Q. A natural BACE1 and GSK3β dual inhibitor Notopterol effectively ameliorates the cognitive deficits in APP/PS1 Alzheimer’s mice by attenuating amyloid‐β and tau pathology. Clin. Transl. Med., 2020, 10(3), e50. doi: 10.1002/ctm2.50 PMID: 32652879
  33. Di Martino, R.M.C.; De Simone, A.; Andrisano, V.; Bisignano, P.; Bisi, A.; Gobbi, S.; Rampa, A.; Fato, R.; Bergamini, C.; Perez, D.I.; Martinez, A.; Bottegoni, G.; Cavalli, A.; Belluti, F. Versatility of the curcumin scaffold: Discovery of potent and balanced dual BACE-1 and GSK-3β inhibitors. J. Med. Chem., 2016, 59(2), 531-544. doi: 10.1021/acs.jmedchem.5b00894 PMID: 26696252
  34. Prati, F.; De Simone, A.; Bisignano, P.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Favia, A.D.; Bottegoni, G.; Martinez, A.; Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery for Alzheimer’s disease: Triazinones as BACE-1 and GSK-3β inhibitors. Angew. Chem. Int. Ed., 2015, 54(5), 1578-1582. doi: 10.1002/anie.201410456 PMID: 25504761
  35. Prati, F.; De Simone, A.; Armirotti, A.; Summa, M.; Pizzirani, D.; Scarpelli, R.; Bertozzi, S.M.; Perez, D.I.; Andrisano, V.; Perez-Castillo, A.; Monti, B.; Massenzio, F.; Polito, L.; Racchi, M.; Sabatino, P.; Bottegoni, G.; Martinez, A.; Cavalli, A.; Bolognesi, M.L. 3,4-Dihydro-1,3,5-triazin-2(1 H)-ones as the First Dual BACE-1/GSK-3β Fragment Hits against Alzheimer’s Disease. ACS Chem. Neurosci., 2015, 6(10), 1665-1682. doi: 10.1021/acschemneuro.5b00121 PMID: 26171616
  36. Cole, S.; Vassar, R. BACE1 structure and function in health and Alzheimer’s disease. Curr. Alzheimer Res., 2008, 5(2), 100-120. doi: 10.2174/156720508783954758 PMID: 18393796
  37. Vassar, R. The β-secretase, BACE: A prime drug target for Alzheimer’s disease. J. Mol. Neurosci., 2001, 17(2), 157-170. doi: 10.1385/JMN:17:2:157 PMID: 11816789
  38. Huang, W.H.; Sheng, R.; Hu, Y.Z. Progress in the development of nonpeptidomimetic BACE 1 inhibitors for Alzheimer’s disease. Curr. Med. Chem., 2009, 16(14), 1806-1820. doi: 10.2174/092986709788186174 PMID: 19442147
  39. Kumar, A.; Srivastava, G.; Negi, A.S.; Sharma, A. Docking, molecular dynamics, binding energy-MM-PBSA studies of naphthofuran derivatives to identify potential dual inhibitors against BACE-1 and GSK-3β. J. Biomol. Struct. Dyn., 2019, 37(2), 275-290. doi: 10.1080/07391102.2018.1426043 PMID: 29310523
  40. Machauer, R.; Lueoend, R.; Hurth, K.; Veenstra, S.J.; Rueeger, H.; Voegtle, M.; Tintelnot-Blomley, M.; Rondeau, J.M.; Jacobson, L.H.; Laue, G.; Beltz, K.; Neumann, U. Discovery of Umibecestat (CNP520): A potent, selective, and efficacious β-secretase (BACE1) inhibitor for the prevention of alzheimer’s disease. J. Med. Chem., 2021, 64(20), 15262-15279. doi: 10.1021/acs.jmedchem.1c01300 PMID: 34648711
  41. Hong, L.; Tang, J. Flap position of free memapsin 2 (β-secretase), a model for flap opening in aspartic protease catalysis. Biochemistry, 2004, 43(16), 4689-4695. doi: 10.1021/bi0498252 PMID: 15096037
  42. Barman, A.; Schürer, S.; Prabhakar, R. Computational modeling of substrate specificity and catalysis of the β-secretase (BACE1) enzyme. Biochemistry, 2011, 50(20), 4337-4349. doi: 10.1021/bi200081h PMID: 21500768
  43. Fujimoto, K.; Matsuoka, E.; Asada, N.; Tadano, G.; Yamamoto, T.; Nakahara, K.; Fuchino, K.; Ito, H.; Kanegawa, N.; Moechars, D.; Gijsen, H.J.M.; Kusakabe, K. Structure-based design of selective β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors: Targeting the flap to gain selectivity over BACE2. J. Med. Chem., 2019, 62(10), 5080-5095. doi: 10.1021/acs.jmedchem.9b00309 PMID: 31021626
  44. Yuan, J.; Venkatraman, S.; Zheng, Y.; McKeever, B.M.; Dillard, L.W.; Singh, S.B. Structure-based design of β-site APP cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer’s disease. J. Med. Chem., 2013, 56(11), 4156-4180. doi: 10.1021/jm301659n PMID: 23509904
  45. Buch, I.; Fishelovitch, D.; London, N.; Raveh, B.; Wolfson, H.J.; Nussinov, R. Allosteric regulation of glycogen synthase kinase 3β: A theoretical study. Biochemistry, 2010, 49(51), 10890-10901. doi: 10.1021/bi100822q PMID: 21105670
  46. Elangovan, N.D.; Dhanabalan, A.K.; Gunasekaran, K.; Kandimalla, R.; Sankarganesh, D. Screening of potential drug for Alzheimer’s disease: A computational study with GSK-3 β inhibition through virtual screening, docking, and molecular dynamics simulation. J. Biomol. Struct. Dyn., 2021, 39(18), 7065-7079. doi: 10.1080/07391102.2020.1805362 PMID: 32779973
  47. He, Q.; Han, C.; Li, G.; Guo, H.; Wang, Y.; Hu, Y.; Lin, Z.; Wang, Y. In silico design novel (5-imidazol-2-yl-4-phenylpyrimidin-2-yl)2-(2-pyridylamino)ethylamine derivatives as inhibitors for glycogen synthase kinase 3 based on 3D-QSAR, molecular docking and molecular dynamics simulation. Comput. Biol. Chem., 2020, 88, 107328. doi: 10.1016/j.compbiolchem.2020.107328 PMID: 32688011
  48. Nassar, H.; Sippl, W.; Dahab, R.A.; Taha, M. Molecular docking, molecular dynamics simulations and in vitro screening reveal cefixime and ceftriaxone as GSK3β covalent inhibitors. RSC Adv., 2023, 13(17), 11278-11290. doi: 10.1039/D3RA01145C PMID: 37057264
  49. Ghosh, S.; Keretsu, S.; Cho, S.J. 3D-QSAR, docking and molecular dynamics simulation study of C-Glycosylflavones as GSK-3β inhibitors. J. Chosun. Nat. Sci., 2020, 13(4), 170-180.
  50. Kumar, A.; Srivastava, G.; Srivastava, S.; Verma, S.; Negi, A.S.; Sharma, A. Investigation of naphthofuran moiety as potential dual inhibitor against BACE-1 and GSK-3β: Molecular dynamics simulations, binding energy, and network analysis to identify first-in-class dual inhibitors against Alzheimer’s disease. J. Mol. Model., 2017, 23(8), 239. doi: 10.1007/s00894-017-3396-7 PMID: 28741112
  51. Kumar, A.; Srivastava, G.; Sharma, A. In silico interaction studies of first dual inhibitor against BACE-1/GSK-3β. In: 2016 International Conference on Bioinformatics and Systems Biology (BSB)., 2016, pp. 1-4. doi: 10.1109/BSB.2016.7552161
  52. ZINC. Available from: https://zinc15.docking.org/substances/subsets/ (cited 2023 Sep 3).
  53. Chapter 18. Discovery of Multi-Target Agents for Neurological Diseases via Ligand Design ⋅ Request PDF. Available from: https://www.researchgate.net/publication/346791653_Chapter_18_Discovery_of_Multi-Target_Agents_for_Neurological_Diseases_via_Ligand_Design (cited 2023 Sep 3).
  54. Domínguez, J.L.; Fernández-Nieto, F.; Castro, M.; Catto, M.; Paleo, M.R.; Porto, S.; Sardina, F.J.; Brea, J.M.; Carotti, A.; Villaverde, M.C.; Sussman, F. Computer-aided structure-based design of multitarget leads for Alzheimer’s disease. J. Chem. Inf. Model., 2015, 55(1), 135-148. doi: 10.1021/ci500555g PMID: 25483751
  55. Raj, U.; Kumar, H.; Gupta, S.; Varadwaj, P.K. Exploring dual inhibitors for STAT1 and STAT5 receptors utilizing virtual screening and dynamics simulation validation. J. Biomol. Struct. Dyn., 2016, 34(10), 2115-2129. doi: 10.1080/07391102.2015.1108870 PMID: 26471877
  56. Ramsay, R.R.; Majekova, M.; Medina, M.; Valoti, M. Key targets for multi-target ligands designed to combat neurodegeneration. Front. Neurosci., 2016, 10, 375. doi: 10.3389/fnins.2016.00375 PMID: 27597816
  57. Pirolli, D.; Righino, B.; Camponeschi, C.; Ria, F.; Di Sante, G.; De Rosa, M.C. Virtual screening and molecular dynamics simulations provide insight into repurposing drugs against SARS-CoV-2 variants Spike protein/ACE2 interface. Sci. Rep., 2023, 13(1), 1494. doi: 10.1038/s41598-023-28716-8 PMID: 36707679
  58. Chander, S.; Pandey, R.K.; Penta, A.; Choudhary, B.S.; Sharma, M.; Malik, R.; Prajapati, V.K.; Murugesan, S. Molecular docking and molecular dynamics simulation based approach to explore the dual inhibitor against HIV-1 reverse transcriptase and integrase. Comb. Chem. High Throughput Screen., 2017, 20(8), 734-746. PMID: 28641512
  59. Manandhar, S.; Pai, K.S.R.; Krishnamurthy, P.T.; Kiran, A.V.V.V.R.; Kumari, G.K. Identification of novel TMPRSS2 inhibitors against SARS-CoV-2 infection: A structure-based virtual screening and molecular dynamics study. Struct. Chem., 2022, 33(5), 1529-1541. doi: 10.1007/s11224-022-01921-3 PMID: 35345416
  60. Baby, K.; Maity, S.; Mehta, C.H.; Suresh, A.; Nayak, U.Y.; Nayak, Y. SARS-CoV-2 entry inhibitors by dual targeting TMPRSS2 and ACE2: An in silico drug repurposing study. Eur. J. Pharmacol., 2021, 896, 173922. doi: 10.1016/j.ejphar.2021.173922 PMID: 33539819
  61. Ivanova, L.; Tammiku-Taul, J.; García-Sosa, A.T.; Sidorova, Y.; Saarma, M.; Karelson, M. Molecular dynamics simulations of the interactions between glial cell line-derived neurotrophic factor family receptor GFRα1 and small-molecule ligands. ACS Omega, 2018, 3(9), 11407-11414. doi: 10.1021/acsomega.8b01524 PMID: 30320260
  62. Docking of FDA Approved Drugs Targeting NSP-16. Docking of FDA Approved Drugs Targeting NSP-16, N-Protein and Main Protease of SARS-CoV-2 as Dual Inhibitors. Biointerface Res. Appl. Chem., 2020, 11(3), 9848-9861. doi: 10.33263/BRIAC113.98489861
  63. P, G.; M K, K. Docking studies and molecular dynamics simulation of triazole benzene sulfonamide derivatives with human carbonic anhydrase IX inhibition activity. RSC Adv., 2021, 11(60), 38079-38093. doi: 10.1039/D1RA07377J PMID: 35498092
  64. Nawaz, M.Z.; Attique, S.A.; Ain, Q.; Alghamdi, H.A.; Bilal, M.; Yan, W.; Zhu, D. Discovery and characterization of dual inhibitors of human Vanin-1 and Vanin-2 enzymes through molecular docking and dynamic simulation-based approach. Int. J. Biol. Macromol., 2022, 213, 1088-1097. doi: 10.1016/j.ijbiomac.2022.06.014 PMID: 35697166
  65. Krishna Swaroop, A.; Krishnan Namboori, P.K.; Esakkimuthukumar, M.; Praveen, T.K.; Nagarjuna, P.; Patnaik, S.K.; Selvaraj, J. Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision. Comput. Biol. Med., 2023, 163, 107231. doi: 10.1016/j.compbiomed.2023.107231 PMID: 37421735

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