Research Article
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Year 2024, Volume: 11 Issue: 4, 1425 - 1440
https://doi.org/10.18596/jotcsa.1465547

Abstract

References

  • 1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules [Internet]. 2020 Dec 8;25(24):5789. Available from: <URL>.
  • 2. Cummings JL. Alzheimer Disease. JAMA [Internet]. 2002 May 8;287(18):2335. Available from: <URL>.
  • 3. Brookmeyer R, Evans DA, Hebert L, Langa KM, Heeringa SG, Plassman BL, et al. National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimer’s Dement [Internet]. 2011 Jan 1;7(1):61–73. Available from: <URL>.
  • 4. Gomez‐Arboledas A, Davila JC, Sanchez‐Mejias E, Navarro V, Nuñez‐Diaz C, Sanchez‐Varo R, et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia [Internet]. 2018 Mar 27;66(3):637–53. Available from: <URL>.
  • 5. Sharoar MG, Hu X, Ma XM, Zhu X, Yan R. Sequential formation of different layers of dystrophic neurites in Alzheimer’s brains. Mol Psychiatry [Internet]. 2019 Sep 21;24(9):1369–82. Available from: <URL>.
  • 6. Rajmohan R, Reddy PH. Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons. J Alzheimer’s Dis [Internet]. 2017 Apr 19;57(4):975–99. Available from: <URL>.
  • 7. Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, et al. Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies. Biomolecules [Internet]. 2016 Jan 6;6(1):6. Available from: <URL>.
  • 8. Ben Zablah Y, Zhang H, Gugustea R, Jia Z. LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases. Cells [Internet]. 2021 Aug 13;10(8):2079. Available from: <URL>.
  • 9. Manetti F. LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators. Med Res Rev [Internet]. 2012 Sep 16;32(5):968–98. Available from: <URL>.
  • 10. Scott RW, Olson MF. LIM kinases: function, regulation and association with human disease. J Mol Med [Internet]. 2007 Jun 10;85(6):555–68. Available from: <URL>.
  • 11. Turab Naqvi AA, Hasan GM, Hassan MI. Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer’s Disease. Curr Top Med Chem [Internet]. 2020 Jun 1;20(12):1059–73. Available from: <URL>.
  • 12. Hiraoka J, Okano I, Higuchi O, Yang N, Mizuno K. Self‐association of LIM‐kinase 1 mediated by the interaction between an N‐terminal LIM domain and a C‐terminal kinase domain. FEBS Lett [Internet]. 1996 Dec 9;399(1–2):117–21. Available from: <URL>.
  • 13. Park J, Kim SW, Cho MC. The Role of LIM Kinase in the Male Urogenital System. Cells [Internet]. 2021 Dec 28;11(1):78. Available from: <URL>.
  • 14. Ding Y, Milosavljevic T, Alahari SK. Nischarin Inhibits LIM Kinase To Regulate Cofilin Phosphorylation and Cell Invasion. Mol Cell Biol [Internet]. 2008 Jun 1;28(11):3742–56. Available from: <URL>.
  • 15. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol [Internet]. 2007 Jan 1;39(6):1071–6. Available from: <URL>.
  • 16. Ohashi K. Roles of cofilin in development and its mechanisms of regulation. Dev Growth Differ [Internet]. 2015 May 10;57(4):275–90. Available from: <URL>.
  • 17. Henderson BW, Greathouse KM, Ramdas R, Walker CK, Rao TC, Bach S V., et al. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid. Sci Signal [Internet]. 2019 Jun 25;12(587):eaaw9318. Available from: <URL>.
  • 18. Singh R, Pokle AV, Ghosh P, Ganeshpurkar A, Swetha R, Singh SK, et al. Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors. J Biomol Struct Dyn [Internet]. 2023 Sep 2;41(13):6089–103. Available from: <URL>.
  • 19. Rangaswamy R, Hemavathy N, Subramaniyan S, Vetrivel U, Jeyakanthan J. Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics. J Biomol Struct Dyn [Internet]. 2023 Dec 8;Article in Press. Available from: <URL>.
  • 20. Zhang M, Wang R, Tian J, Song M, Zhao R, Liu K, et al. Targeting LIMK1 with luteolin inhibits the growth of lung cancer in vitro and in vivo. J Cell Mol Med [Internet]. 2021 Jun 13;25(12):5560–71. Available from: <URL>.
  • 21. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep [Internet]. 2017 Mar 3;7(1):42717. Available from: <URL>.
  • 22. Chen X, Li H, Tian L, Li Q, Luo J, Zhang Y. Analysis of the Physicochemical Properties of Acaricides Based on Lipinski’s Rule of Five. J Comput Biol [Internet]. 2020 Sep 1;27(9):1397–406. Available from: <URL>.
  • 23. Meihua Rose Feng BSP. Assessment of Blood-Brain Barrier Penetration: In Silico, In Vitro and In Vivo. Curr Drug Metab [Internet]. 2002 Dec 1;3(6):647–57. Available from: <URL>.
  • 24. Ejeh S, Uzairu A, Shallangwa GA, Abechi SE. In Silico Design, Drug-Likeness and ADMET Properties Estimation of Some Substituted Thienopyrimidines as HCV NS3/4A Protease Inhibitors. Chem Africa [Internet]. 2021 Sep 17;4(3):563–74. Available from: <URL>.
  • 25. Humphreys SC, Davis JA, Iqbal S, Kamel A, Kulmatycki K, Lao Y, et al. Considerations and recommendations for assessment of plasma protein binding and drug–drug interactions for siRNA therapeutics. Nucleic Acids Res [Internet]. 2022 Jun 24;50(11):6020–37. Available from: <URL>.
  • 26. Khan T, Dixit S, Ahmad R, Raza S, Azad I, Joshi S, et al. Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes. J Chem Biol [Internet]. 2017 Jul 4;10(3):91–104. Available from: <URL>.
  • 27. Tariq M, Sirajuddin M, Ali S, Khalid N, Tahir MN, Khan H, et al. Pharmacological investigations and Petra/Osiris/Molinspiration (POM) analyses of newly synthesized potentially bioactive organotin(IV) carboxylates. J Photochem Photobiol B Biol [Internet]. 2016 May 1;158:174–83. Available from: <URL>.
  • 28. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX [Internet]. 2015 Sep 1;1–2:19–25. Available from: <URL>.
  • 29. Rakhshani H, Dehghanian E, Rahati A. Enhanced GROMACS: toward a better numerical simulation framework. J Mol Model [Internet]. 2019 Dec 25;25(12):355. Available from: <URL>.
  • 30. Parra-Cruz R, Jäger CM, Lau PL, Gomes RL, Pordea A. Rational Design of Thermostable Carbonic Anhydrase Mutants Using Molecular Dynamics Simulations. J Phys Chem B [Internet]. 2018 Sep 13;122(36):8526–36. Available from: <URL>.
  • 31. Das NC, Labala RK, Patra R, Chattoraj A, Mukherjee S. In Silico Identification of New Anti-SARS-CoV-2 Agents from Bioactive Phytocompounds Targeting the Viral Spike Glycoprotein and Human TLR4. Lett Drug Des Discov [Internet]. 2022 Mar 7;19(3):175–91. Available from: <URL>.
  • 32. Liu P, Lu J, Yu H, Ren N, Lockwood FE, Wang QJ. Lubricant shear thinning behavior correlated with variation of radius of gyration via molecular dynamics simulations. J Chem Phys [Internet]. 2017 Aug 28;147(8):84904. Available from: <URL>.
  • 33. Singh VK, Chaurasia H, Kumari P, Som A, Mishra R, Srivastava R, et al. Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2. J Biomol Struct Dyn [Internet]. 2022 Dec 5;40(21):10519–42. Available from: <URL>.

Targeting LIMK1 in Alzheimer's Disease: A Multifaceted Computational Investigation Involving ADMET, Virtual Screening, Molecular Docking, and Molecular Dynamics

Year 2024, Volume: 11 Issue: 4, 1425 - 1440
https://doi.org/10.18596/jotcsa.1465547

Abstract

LIM domain kinases (LIMKs), which include LIMK1 and LIMK2, are key proteins in actin dynamics. On this basis, the inhibition of LIMK1 enhances dendritic spine density and size in dementia, reducing Alzheimer's disease (AD) effects. Therefore, several small molecules were discovered as potential therapeutic targets for AD. Herein, a pharmacophore-based virtual screening was employed to identify novel potential LIMK1 inhibitors. The pharmacophore model derived from the co-crystallized receptor structure of PubChem-329823760: LIMK1 (PDB ID: 5NXC) was then used for virtual screening. After applying Lipinski's rules and pharmacophore filters, 29 potential hits were identified. Molecular docking simulations were performed to determine the binding affinities of these candidates against LIMK1, with results ranging from -5.20 to -10.60 kcal/mol. Notably, PubChem-136621040 showed the highest binding affinity against the target protein, with a docking score of -10.60 kcal/mol, slightly surpassing the native ligand, PubChem-329823760, possessing a lower docking score of -9.80 kcal/mol. The drug-likeness and toxicity properties of target compounds were assessed through ADMET evaluations. A series of 75 nanosecond molecular dynamics (MD) simulations were conducted on the complexes generated by the best-docked molecule and the native ligand. RMSD, RMSF, SASA, and Rg calculations of their trajectories were also calculated. PubChem-136621040 possessed an average RMSD value of 0.23 nm, lower than the native ligand's 0.31 nm, indicating a greater binding stability. The RMSF results also revealed that the best-docked compound had a lower value (0.10 nm), while the native ligand possessed a value of 0.12 nm. The SASA values for both the native ligand and the best-docked compound were nearly identical, at 150.20 nm2 and 150.80 nm2, respectively. The Rg results demonstrated that both complexes maintained their rigidity throughout the simulation, with similar average values of 2.04 nm for the native ligand and 2.06 nm for the best-docked compound.

Thanks

The computational calculations were executed at TUBITAK-ULAKBIM High Performance and Grid Computing Centre (TRUBA).

References

  • 1. Breijyeh Z, Karaman R. Comprehensive Review on Alzheimer’s Disease: Causes and Treatment. Molecules [Internet]. 2020 Dec 8;25(24):5789. Available from: <URL>.
  • 2. Cummings JL. Alzheimer Disease. JAMA [Internet]. 2002 May 8;287(18):2335. Available from: <URL>.
  • 3. Brookmeyer R, Evans DA, Hebert L, Langa KM, Heeringa SG, Plassman BL, et al. National estimates of the prevalence of Alzheimer’s disease in the United States. Alzheimer’s Dement [Internet]. 2011 Jan 1;7(1):61–73. Available from: <URL>.
  • 4. Gomez‐Arboledas A, Davila JC, Sanchez‐Mejias E, Navarro V, Nuñez‐Diaz C, Sanchez‐Varo R, et al. Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer’s disease. Glia [Internet]. 2018 Mar 27;66(3):637–53. Available from: <URL>.
  • 5. Sharoar MG, Hu X, Ma XM, Zhu X, Yan R. Sequential formation of different layers of dystrophic neurites in Alzheimer’s brains. Mol Psychiatry [Internet]. 2019 Sep 21;24(9):1369–82. Available from: <URL>.
  • 6. Rajmohan R, Reddy PH. Amyloid-Beta and Phosphorylated Tau Accumulations Cause Abnormalities at Synapses of Alzheimer’s disease Neurons. J Alzheimer’s Dis [Internet]. 2017 Apr 19;57(4):975–99. Available from: <URL>.
  • 7. Šimić G, Babić Leko M, Wray S, Harrington C, Delalle I, Jovanov-Milošević N, et al. Tau Protein Hyperphosphorylation and Aggregation in Alzheimer’s Disease and Other Tauopathies, and Possible Neuroprotective Strategies. Biomolecules [Internet]. 2016 Jan 6;6(1):6. Available from: <URL>.
  • 8. Ben Zablah Y, Zhang H, Gugustea R, Jia Z. LIM-Kinases in Synaptic Plasticity, Memory, and Brain Diseases. Cells [Internet]. 2021 Aug 13;10(8):2079. Available from: <URL>.
  • 9. Manetti F. LIM kinases are attractive targets with many macromolecular partners and only a few small molecule regulators. Med Res Rev [Internet]. 2012 Sep 16;32(5):968–98. Available from: <URL>.
  • 10. Scott RW, Olson MF. LIM kinases: function, regulation and association with human disease. J Mol Med [Internet]. 2007 Jun 10;85(6):555–68. Available from: <URL>.
  • 11. Turab Naqvi AA, Hasan GM, Hassan MI. Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer’s Disease. Curr Top Med Chem [Internet]. 2020 Jun 1;20(12):1059–73. Available from: <URL>.
  • 12. Hiraoka J, Okano I, Higuchi O, Yang N, Mizuno K. Self‐association of LIM‐kinase 1 mediated by the interaction between an N‐terminal LIM domain and a C‐terminal kinase domain. FEBS Lett [Internet]. 1996 Dec 9;399(1–2):117–21. Available from: <URL>.
  • 13. Park J, Kim SW, Cho MC. The Role of LIM Kinase in the Male Urogenital System. Cells [Internet]. 2021 Dec 28;11(1):78. Available from: <URL>.
  • 14. Ding Y, Milosavljevic T, Alahari SK. Nischarin Inhibits LIM Kinase To Regulate Cofilin Phosphorylation and Cell Invasion. Mol Cell Biol [Internet]. 2008 Jun 1;28(11):3742–56. Available from: <URL>.
  • 15. Bernard O. Lim kinases, regulators of actin dynamics. Int J Biochem Cell Biol [Internet]. 2007 Jan 1;39(6):1071–6. Available from: <URL>.
  • 16. Ohashi K. Roles of cofilin in development and its mechanisms of regulation. Dev Growth Differ [Internet]. 2015 May 10;57(4):275–90. Available from: <URL>.
  • 17. Henderson BW, Greathouse KM, Ramdas R, Walker CK, Rao TC, Bach S V., et al. Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid. Sci Signal [Internet]. 2019 Jun 25;12(587):eaaw9318. Available from: <URL>.
  • 18. Singh R, Pokle AV, Ghosh P, Ganeshpurkar A, Swetha R, Singh SK, et al. Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors. J Biomol Struct Dyn [Internet]. 2023 Sep 2;41(13):6089–103. Available from: <URL>.
  • 19. Rangaswamy R, Hemavathy N, Subramaniyan S, Vetrivel U, Jeyakanthan J. Harnessing allosteric inhibition: prioritizing LIMK2 inhibitors for targeted cancer therapy through pharmacophore-based virtual screening and essential molecular dynamics. J Biomol Struct Dyn [Internet]. 2023 Dec 8;Article in Press. Available from: <URL>.
  • 20. Zhang M, Wang R, Tian J, Song M, Zhao R, Liu K, et al. Targeting LIMK1 with luteolin inhibits the growth of lung cancer in vitro and in vivo. J Cell Mol Med [Internet]. 2021 Jun 13;25(12):5560–71. Available from: <URL>.
  • 21. Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep [Internet]. 2017 Mar 3;7(1):42717. Available from: <URL>.
  • 22. Chen X, Li H, Tian L, Li Q, Luo J, Zhang Y. Analysis of the Physicochemical Properties of Acaricides Based on Lipinski’s Rule of Five. J Comput Biol [Internet]. 2020 Sep 1;27(9):1397–406. Available from: <URL>.
  • 23. Meihua Rose Feng BSP. Assessment of Blood-Brain Barrier Penetration: In Silico, In Vitro and In Vivo. Curr Drug Metab [Internet]. 2002 Dec 1;3(6):647–57. Available from: <URL>.
  • 24. Ejeh S, Uzairu A, Shallangwa GA, Abechi SE. In Silico Design, Drug-Likeness and ADMET Properties Estimation of Some Substituted Thienopyrimidines as HCV NS3/4A Protease Inhibitors. Chem Africa [Internet]. 2021 Sep 17;4(3):563–74. Available from: <URL>.
  • 25. Humphreys SC, Davis JA, Iqbal S, Kamel A, Kulmatycki K, Lao Y, et al. Considerations and recommendations for assessment of plasma protein binding and drug–drug interactions for siRNA therapeutics. Nucleic Acids Res [Internet]. 2022 Jun 24;50(11):6020–37. Available from: <URL>.
  • 26. Khan T, Dixit S, Ahmad R, Raza S, Azad I, Joshi S, et al. Molecular docking, PASS analysis, bioactivity score prediction, synthesis, characterization and biological activity evaluation of a functionalized 2-butanone thiosemicarbazone ligand and its complexes. J Chem Biol [Internet]. 2017 Jul 4;10(3):91–104. Available from: <URL>.
  • 27. Tariq M, Sirajuddin M, Ali S, Khalid N, Tahir MN, Khan H, et al. Pharmacological investigations and Petra/Osiris/Molinspiration (POM) analyses of newly synthesized potentially bioactive organotin(IV) carboxylates. J Photochem Photobiol B Biol [Internet]. 2016 May 1;158:174–83. Available from: <URL>.
  • 28. Abraham MJ, Murtola T, Schulz R, Páll S, Smith JC, Hess B, et al. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers. SoftwareX [Internet]. 2015 Sep 1;1–2:19–25. Available from: <URL>.
  • 29. Rakhshani H, Dehghanian E, Rahati A. Enhanced GROMACS: toward a better numerical simulation framework. J Mol Model [Internet]. 2019 Dec 25;25(12):355. Available from: <URL>.
  • 30. Parra-Cruz R, Jäger CM, Lau PL, Gomes RL, Pordea A. Rational Design of Thermostable Carbonic Anhydrase Mutants Using Molecular Dynamics Simulations. J Phys Chem B [Internet]. 2018 Sep 13;122(36):8526–36. Available from: <URL>.
  • 31. Das NC, Labala RK, Patra R, Chattoraj A, Mukherjee S. In Silico Identification of New Anti-SARS-CoV-2 Agents from Bioactive Phytocompounds Targeting the Viral Spike Glycoprotein and Human TLR4. Lett Drug Des Discov [Internet]. 2022 Mar 7;19(3):175–91. Available from: <URL>.
  • 32. Liu P, Lu J, Yu H, Ren N, Lockwood FE, Wang QJ. Lubricant shear thinning behavior correlated with variation of radius of gyration via molecular dynamics simulations. J Chem Phys [Internet]. 2017 Aug 28;147(8):84904. Available from: <URL>.
  • 33. Singh VK, Chaurasia H, Kumari P, Som A, Mishra R, Srivastava R, et al. Design, synthesis, and molecular dynamics simulation studies of quinoline derivatives as protease inhibitors against SARS-CoV-2. J Biomol Struct Dyn [Internet]. 2022 Dec 5;40(21):10519–42. Available from: <URL>.
There are 33 citations in total.

Details

Primary Language English
Subjects Computational Chemistry, Molecular Medicine
Journal Section RESEARCH ARTICLES
Authors

Defne Eşkin 0009-0007-8399-0626

Harun Nalçakan 0000-0003-3821-8681

Gülbin Kurtay 0000-0003-0920-8409

Yiğit Akkan 0009-0003-9958-9651

Mazlum Türk 0000-0003-1683-9284

Beril Uras 0009-0005-4900-8470

Publication Date
Submission Date April 5, 2024
Acceptance Date September 6, 2024
Published in Issue Year 2024 Volume: 11 Issue: 4

Cite

Vancouver Eşkin D, Nalçakan H, Kurtay G, Akkan Y, Türk M, Uras B. Targeting LIMK1 in Alzheimer’s Disease: A Multifaceted Computational Investigation Involving ADMET, Virtual Screening, Molecular Docking, and Molecular Dynamics. JOTCSA. 11(4):1425-40.