Research Article
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New Drug Design to Suppress Nonalcoholic Steatohepatitis

Year 2024, Volume: 11 Issue: 2, 585 - 590, 15.05.2024

Soykan Agar Barbaros Akkurt Engin Ulukaya

https://doi.org/10.18596/jotcsa.1395403

Abstract

A de novo designed biomolecule called INASHD was utilized through computer-aided drug design techniques to specifically target β2-spectrin, effectively suppressing and preventing NASH disease. Advanced computational software tools concerning the technologies of molecular docking and molecular dynamics (MD), were employed to showcase the drug's remarkable ability to efficiently suppress and control the α-helical topology of β2-spectrin. This protein is a vital component within the disease pathway. We successfully devised an effective design suppressing β2-spectrin, exhibiting an inhibition score surpassing any other molecule documented in scientific literature. With robust support from validated computational software, this bioorganic structure holds significant value and can be applied for a patent due to its innovative design. It shows promising potential for delivering positive outcomes in various stages, including in vitro, in vivo, ex vivo, and human phase studies.

Keywords

Nonalcoholic steatohepatitis In silico drug design molecular docking molecular dynamics beta-spectrin

Thanks

This study was funded by Molecular Cancer Research Association at Istinye University under the oncology & medical biochemistry team of Prof. Engin Ulukaya (M.D. Ph.D.).

References

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  • 2. Maldonado FHR, Mega PF, Germano CW, Dias LLC, Callejas GH, Gestic MA, et al. Impact of pre-operative weight loss on non-alcoholic fatty liver disease histopathology and insulin resistance in individuals undergoing bariatric surgery: a propensity matched cross-sectional comparison. Sao Paulo Med J [Internet]. 2024;142(1):e2022663. Available from: <URL>.
  • 3. Tabaeian SP, Rezapour A, Azari S, Martini M, Saran M, Behzadifar M, et al. Prevalence of Non-alcoholic Fatty Liver Disease in Iran: A Systematic Review and Meta-analysis. J Clin Exp Hepatol [Internet]. 2024 Jan 1;14(1):101209. Available from: <URL>.
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  • 6. Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, et al. β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Sci Transl Med [Internet]. 2021 Dec 15;13(624):eabk2267. Available from: <URL>.
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  • 9. De Matteis MA, Morrow JS. Spectrin tethers and mesh in the biosynthetic pathway. J Cell Sci [Internet]. 2000 Jul 1;113(13):2331–43. Available from: <URL>.
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  • 14. Gaillard T. Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark. J Chem Inf Model [Internet]. 2018 Aug 27;58(8):1697–706. Available from: <URL>.
  • 15. Şenel P, Agar S, Sayin VO, Altay F, Yurtsever M, Gölcü A. Elucidation of binding interactions and mechanism of Fludarabine with dsDNA via multispectroscopic and molecular docking studies. J Pharm Biomed Anal [Internet]. 2020 Feb 5;179:112994. Available from: <URL>.
  • 16. Şenel P, Agar S, İş YS, Altay F, Gölcü A, Yurtsever M. Deciphering the mechanism and binding interactions of Pemetrexed with dsDNA with DNA-targeted chemotherapeutics via spectroscopic, analytical, and simulation studies. J Pharm Biomed Anal [Internet]. 2022 Feb 5;209:114490. Available from: <URL>.
  • 17. Cheraghi S, Şenel P, Dogan Topal B, Agar S, Majidian M, Yurtsever M, et al. Elucidation of DNA-Eltrombopag Binding: Electrochemical, Spectroscopic and Molecular Docking Techniques. Biosensors [Internet]. 2023 Feb 21;13(3):300. Available from: <URL>.
  • 18. Şenel P, Agar S, Yurtsever M, Gölcü A. Voltammetric quantification, spectroscopic, and DFT studies on the binding of the antineoplastic drug Azacitidine with DNA. J Pharm Biomed Anal [Internet]. 2024 Jan 5;237:115746. Available from: <URL>.
  • 19. Desmond D. Desmond. New York: Shaw Research; 2017.
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  • 21. Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys [Internet]. 1994 Sep 1;101(5):4177–89. Available from: <URL>.

Year 2024, Volume: 11 Issue: 2, 585 - 590, 15.05.2024

Soykan Agar Barbaros Akkurt Engin Ulukaya

https://doi.org/10.18596/jotcsa.1395403

Abstract

References

  • 1. Lahmi A, Oryan S, Eidi A, Rohani AH. Comparative effects of thymol and vitamin E on nonalcoholic fatty liver disease in male Wistar rats. Brazilian J Biol [Internet]. 2024;84:e268781. Available from: <URL>.
  • 2. Maldonado FHR, Mega PF, Germano CW, Dias LLC, Callejas GH, Gestic MA, et al. Impact of pre-operative weight loss on non-alcoholic fatty liver disease histopathology and insulin resistance in individuals undergoing bariatric surgery: a propensity matched cross-sectional comparison. Sao Paulo Med J [Internet]. 2024;142(1):e2022663. Available from: <URL>.
  • 3. Tabaeian SP, Rezapour A, Azari S, Martini M, Saran M, Behzadifar M, et al. Prevalence of Non-alcoholic Fatty Liver Disease in Iran: A Systematic Review and Meta-analysis. J Clin Exp Hepatol [Internet]. 2024 Jan 1;14(1):101209. Available from: <URL>.
  • 4. Manne V, Handa P, Kowdley K V. Pathophysiology of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis. Clin Liver Dis [Internet]. 2018 Feb 1;22(1):23–37. Available from: <URL>.
  • 5. Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S. Nonalcoholic Steatohepatitis. JAMA [Internet]. 2020 Mar 24;323(12):1175–83. Available from: <URL>.
  • 6. Rao S, Yang X, Ohshiro K, Zaidi S, Wang Z, Shetty K, et al. β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development. Sci Transl Med [Internet]. 2021 Dec 15;13(624):eabk2267. Available from: <URL>.
  • 7. Bennett V, Lorenzo DN. Spectrin- and Ankyrin-Based Membrane Domains and the Evolution of Vertebrates. In: Current Topics in Membranes [Internet]. Academic Press; 2013. p. 1–37. Available from: <URL>.
  • 8. Bennett V, Lorenzo DN. An Adaptable Spectrin/Ankyrin-Based Mechanism for Long-Range Organization of Plasma Membranes in Vertebrate Tissues. In: Current Topics in Membranes [Internet]. Academic Press; 2016. p. 143–84. Available from: <URL>.
  • 9. De Matteis MA, Morrow JS. Spectrin tethers and mesh in the biosynthetic pathway. J Cell Sci [Internet]. 2000 Jul 1;113(13):2331–43. Available from: <URL>.
  • 10. Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, et al. Gaussian 09, Revision D.01. Wallingford, CT: Gaussian, Inc.; 2009.
  • 11. Becke AD. Density-functional thermochemistry. III. The role of exact exchange. J Chem Phys [Internet]. 1993 Apr 1;98(7):5648–52. Available from: <URL>.
  • 12. Dennington R, Keith TA, Millam JM. GaussView Version 6. 2019.
  • 13. Hanwell MD, Curtis DE, Lonie DC, Vandermeersch T, Zurek E, Hutchison GR. Avogadro: an advanced semantic chemical editor, visualization, and analysis platform. J Cheminform [Internet]. 2012 Dec 13;4(1):17. Available from: <URL>.
  • 14. Gaillard T. Evaluation of AutoDock and AutoDock Vina on the CASF-2013 Benchmark. J Chem Inf Model [Internet]. 2018 Aug 27;58(8):1697–706. Available from: <URL>.
  • 15. Şenel P, Agar S, Sayin VO, Altay F, Yurtsever M, Gölcü A. Elucidation of binding interactions and mechanism of Fludarabine with dsDNA via multispectroscopic and molecular docking studies. J Pharm Biomed Anal [Internet]. 2020 Feb 5;179:112994. Available from: <URL>.
  • 16. Şenel P, Agar S, İş YS, Altay F, Gölcü A, Yurtsever M. Deciphering the mechanism and binding interactions of Pemetrexed with dsDNA with DNA-targeted chemotherapeutics via spectroscopic, analytical, and simulation studies. J Pharm Biomed Anal [Internet]. 2022 Feb 5;209:114490. Available from: <URL>.
  • 17. Cheraghi S, Şenel P, Dogan Topal B, Agar S, Majidian M, Yurtsever M, et al. Elucidation of DNA-Eltrombopag Binding: Electrochemical, Spectroscopic and Molecular Docking Techniques. Biosensors [Internet]. 2023 Feb 21;13(3):300. Available from: <URL>.
  • 18. Şenel P, Agar S, Yurtsever M, Gölcü A. Voltammetric quantification, spectroscopic, and DFT studies on the binding of the antineoplastic drug Azacitidine with DNA. J Pharm Biomed Anal [Internet]. 2024 Jan 5;237:115746. Available from: <URL>.
  • 19. Desmond D. Desmond. New York: Shaw Research; 2017.
  • 20. Evans DJ, Holian BL. The Nose–Hoover thermostat. J Chem Phys [Internet]. 1985 Oct 15;83(8):4069–74. Available from: <URL>.
  • 21. Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phys [Internet]. 1994 Sep 1;101(5):4177–89. Available from: <URL>.
There are 21 citations in total.

Details

Primary Language English
Subjects Computational Chemistry
Journal Section RESEARCH ARTICLES
Authors

Soykan Agar 0000-0002-9870-6882

Barbaros Akkurt 0000-0003-4066-3004

Engin Ulukaya 0000-0003-4875-5472

Publication Date May 15, 2024
Submission Date November 24, 2023
Acceptance Date January 23, 2024
Published in Issue Year 2024 Volume: 11 Issue: 2

Cite

Vancouver Agar S, Akkurt B, Ulukaya E. New Drug Design to Suppress Nonalcoholic Steatohepatitis. JOTCSA. 2024;11(2):585-90.
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