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Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening

Year 2024, , 1 - 11, 21.05.2024
https://doi.org/10.33435/tcandtc.1224592

Abstract

Sirtuins family are a Nicotinamide Adenine Dinucleotide (NAD+) dependent histone deacetylase enzyme. Sirtuins have been implicated in the pathogenesis of various diseases including cancer, neurological disorders and metabolic syndromes, hence sirtuins appointed as a promising therapeutic target for diseases, by regulating of its activity by small molecules modulators. The indole containing selisistat (EX-527) and its derivatives set as the most potent and selective SIRT1 inhibitors. Selisistat showed an effective sirtuin inhibition on various cancer cell line, and has reached the clinical trials for endometriosis and Huntington’s disease. In this study a set of selisistat derivatives were designed and virtually studied by means of molecular docking, ADMET, and molecular dynamics (MD) simulations. Two molecules were showed promising virtual binding affinity on the SIRT1-3 proteins. Compound 1 exhibits stronger in silico SIRT1 and SIRT2 affinities than EX-527, whereas compound 8 prefers SIRT3 binding. The ADMET analysis of the virtually active molecules demonstrated an acceptable drug-like profile and desirable pharmacokinetics properties. The MD simulation analysis revealed that compound 1 had significantly better alignment with SIRT1 and SIRT2 proteins than EX-527 according to Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) data, while compound 8 had a perfect alignment and fitting with SIRT3 protein than EX-527.

Supporting Institution

Collage of pharmacy

References

  • [1] L. F. Costa-Machado, P. J. Fernandez-Marcos, The sirtuin family in cancer, Cell Cycle. 18 (2019) 2164–2196.
  • [2] S. Rahayu, S. Prasetyawan, S. Widyarti, M. F. Atho’illah, G. Ciptadi, Computational study on the effectiveness of flavonoids from Marsilea crenata C. Presl as potent SIRT1 activators and NFκB Inhibitors, Karbala International Journal of Modern Science. 8 (2022).
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  • [4] R. Pratiwi, V. Prachayasittikul, S. Prachayasittikul, C. Nantasenamat, Rational design of novel sirtuin 1 activators via structure-activity insights from application of QSAR modeling, EXCLI J. 18 (2019) 207–222.
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  • [6] R. Manjula, N. Gokhale, S. Unni, P. Deshmukh, R. Reddyrajula, M. M. Srinivas Bharath, et al, Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2, Bioorg Chem. (2019).
  • [7] T. Seifert, M. Malo, T. Kokkola, E. J. L. Stéen, K. Meinander, E. A. A. Wallén, et al, A scaffold replacement approach towards new sirtuin 2 inhibitors, Bioorg Med Chem. 28 (2020).
  • [8] M. Rahnasto-Rilla, J. Tyni, M. Lahtela-Kakkonen, Sirtuin Inhibitors and Activators, In: Topics in Medicinal Chemistry, Springer. (2020) 55–92.
  • [9] S. D. Süssmuth, S. Haider, G. B. Landwehrmeyer, R. Farmer, C. Frost, G. Tripepi, et al, an exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s disease, Br J Clin Pharmacol. 79 (2015) 465–476.
  • [10] S. Broussy, H. Laaroussi, M. Vidal, Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat), Journal of Enzyme Inhibition and Medicinal Chemistry. 35 (2020) 1124–1136.
  • [11] X. Zhao, D. Allison, B. Condon, F. Zhang, T. Gheyi, A. Zhang, et al, the 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD +) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition, J Med Chem. 56 (2013) 963–969.
  • [12] J. Hu, H. Jing, H. Lin, Sirtuin inhibitors as anticancer agents, Future Medicinal Chemistry, Future Science. 6 (2014) 945–966.
  • [13] S. S. Mahajan, V. Leko, J. A. Simon, A. Bedalov, Sirtuin modulators, Handb Exp Pharmacol. 206 (2011) 241–255.
  • [14] T. Rumpf, S. Gerhardt, O. Einsle, M. Jung, Seeding for sirtuins: Microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking, Acta Crystallographica Section:F Structural Biology Communications. 71 (2015) 1498–1510.
  • [15] J. S. Disch, G. Evindar, C. H. Chiu, C. A. Blum, H. Dai, L. Jin, et al, Discovery of thieno [3,2-d] pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3, J Med Chem. 56 (2013) 3666–3679.
  • [16] G. Madhavi Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman, Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments, J Comput Aided Mol Des. 27 (2013) 221–234.
  • [17] R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J Med Chem. 49 (2006) 6177–6196.
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  • [20] R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, et al, Glide: A New Approach for Rapid, Accurate Docking and Scoring, Method and Assessment of Docking Accuracy, J. Med. Chem. 47 (2004) 1739–1749.
  • [21] QikProp, Schrödinger, LLC, New York, NY (2021).
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  • [23] Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, 2021, Maestro-Desmond Interoperability Tools, Schrödinger, New York, NY (2021).
  • [24] S. Zhao, Y. Y. Zhu, X. Y. Wang, Y. S. Liu, Y. X. Sun, Q. J. Zhao, et al, Structural insight into the interactions between structurally similar inhibitors and SIRT6, Int J. Mol Sci. 21 (2020).
Year 2024, , 1 - 11, 21.05.2024
https://doi.org/10.33435/tcandtc.1224592

Abstract

References

  • [1] L. F. Costa-Machado, P. J. Fernandez-Marcos, The sirtuin family in cancer, Cell Cycle. 18 (2019) 2164–2196.
  • [2] S. Rahayu, S. Prasetyawan, S. Widyarti, M. F. Atho’illah, G. Ciptadi, Computational study on the effectiveness of flavonoids from Marsilea crenata C. Presl as potent SIRT1 activators and NFκB Inhibitors, Karbala International Journal of Modern Science. 8 (2022).
  • [3] X. Hu, W. Zheng, Chemical Probes in Sirtuin Research, in Progress in Molecular Biology and Translational Science, Elsevier B.V. (2018) 1–24.
  • [4] R. Pratiwi, V. Prachayasittikul, S. Prachayasittikul, C. Nantasenamat, Rational design of novel sirtuin 1 activators via structure-activity insights from application of QSAR modeling, EXCLI J. 18 (2019) 207–222.
  • [5] L. J. Talib, M. G. Al-Abbassi, B. T. Al-Sudani, Effect of sirt1 activators on human follicular thyroid cancer, International Journal of Pharmaceutical Research. 12 (2020) 1608–1620.
  • [6] R. Manjula, N. Gokhale, S. Unni, P. Deshmukh, R. Reddyrajula, M. M. Srinivas Bharath, et al, Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2, Bioorg Chem. (2019).
  • [7] T. Seifert, M. Malo, T. Kokkola, E. J. L. Stéen, K. Meinander, E. A. A. Wallén, et al, A scaffold replacement approach towards new sirtuin 2 inhibitors, Bioorg Med Chem. 28 (2020).
  • [8] M. Rahnasto-Rilla, J. Tyni, M. Lahtela-Kakkonen, Sirtuin Inhibitors and Activators, In: Topics in Medicinal Chemistry, Springer. (2020) 55–92.
  • [9] S. D. Süssmuth, S. Haider, G. B. Landwehrmeyer, R. Farmer, C. Frost, G. Tripepi, et al, an exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s disease, Br J Clin Pharmacol. 79 (2015) 465–476.
  • [10] S. Broussy, H. Laaroussi, M. Vidal, Biochemical mechanism and biological effects of the inhibition of silent information regulator 1 (SIRT1) by EX-527 (SEN0014196 or selisistat), Journal of Enzyme Inhibition and Medicinal Chemistry. 35 (2020) 1124–1136.
  • [11] X. Zhao, D. Allison, B. Condon, F. Zhang, T. Gheyi, A. Zhang, et al, the 2.5 Å crystal structure of the SIRT1 catalytic domain bound to nicotinamide adenine dinucleotide (NAD +) and an indole (EX527 analogue) reveals a novel mechanism of histone deacetylase inhibition, J Med Chem. 56 (2013) 963–969.
  • [12] J. Hu, H. Jing, H. Lin, Sirtuin inhibitors as anticancer agents, Future Medicinal Chemistry, Future Science. 6 (2014) 945–966.
  • [13] S. S. Mahajan, V. Leko, J. A. Simon, A. Bedalov, Sirtuin modulators, Handb Exp Pharmacol. 206 (2011) 241–255.
  • [14] T. Rumpf, S. Gerhardt, O. Einsle, M. Jung, Seeding for sirtuins: Microseed matrix seeding to obtain crystals of human Sirt3 and Sirt2 suitable for soaking, Acta Crystallographica Section:F Structural Biology Communications. 71 (2015) 1498–1510.
  • [15] J. S. Disch, G. Evindar, C. H. Chiu, C. A. Blum, H. Dai, L. Jin, et al, Discovery of thieno [3,2-d] pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2, and SIRT3, J Med Chem. 56 (2013) 3666–3679.
  • [16] G. Madhavi Sastry, M. Adzhigirey, T. Day, R. Annabhimoju, W. Sherman, Protein and ligand preparation: Parameters, protocols, and influence on virtual screening enrichments, J Comput Aided Mol Des. 27 (2013) 221–234.
  • [17] R. A. Friesner, R. B. Murphy, M. P. Repasky, L. L. Frye, J. R. Greenwood, T. A. Halgren, et al. Extra precision glide: Docking and scoring incorporating a model of hydrophobic enclosure for protein-ligand complexes, J Med Chem. 49 (2006) 6177–6196.
  • [18] LigPrep, Schrödinger, LLC, New York, NY (2021).
  • [19] T. A. Halgren, R. B. Murphy, R. A. Friesner, H. S. Beard, L. L. Frye, W. T. Pollard, J. L. Banks, Glide: A New Approach for Rapid, Accurate Docking and Scoring, Enrichment Factors in Database Screening, J. Med. Chem. 47 (2004) 1750–1759.
  • [20] R. A. Friesner, J. L. Banks, R. B. Murphy, T. A. Halgren, J. J. Klicic, D. T. Mainz, et al, Glide: A New Approach for Rapid, Accurate Docking and Scoring, Method and Assessment of Docking Accuracy, J. Med. Chem. 47 (2004) 1739–1749.
  • [21] QikProp, Schrödinger, LLC, New York, NY (2021).
  • [22] K. J. Bowers, E. Chow, Xu. Huafeng, R. O. Dror, M. P. Eastwood, B. A. Gregersen, et al, Scalable Algorithms for Molecular Dynamics Simulations on Commodity Clusters, Supercomputing, 2006. SC'06. Proceedings of the ACM/EEEI. (2006).
  • [23] Desmond Molecular Dynamics System, D. E. Shaw Research, New York, NY, 2021, Maestro-Desmond Interoperability Tools, Schrödinger, New York, NY (2021).
  • [24] S. Zhao, Y. Y. Zhu, X. Y. Wang, Y. S. Liu, Y. X. Sun, Q. J. Zhao, et al, Structural insight into the interactions between structurally similar inhibitors and SIRT6, Int J. Mol Sci. 21 (2020).
There are 24 citations in total.

Details

Primary Language English
Subjects Chemical Engineering
Journal Section Research Article
Authors

Yahya Hasan 0000-0002-6782-5897

Ayad Al-hamashi 0000-0001-7522-8390

Early Pub Date July 4, 2023
Publication Date May 21, 2024
Submission Date December 26, 2022
Published in Issue Year 2024

Cite

APA Hasan, Y., & Al-hamashi, A. (2024). Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Computational and Theoretical Chemistry, 8(2), 1-11. https://doi.org/10.33435/tcandtc.1224592
AMA Hasan Y, Al-hamashi A. Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Comp Theo Chem (TC&TC). May 2024;8(2):1-11. doi:10.33435/tcandtc.1224592
Chicago Hasan, Yahya, and Ayad Al-hamashi. “Identification of Selisistat Derivatives As SIRT1-3 Inhibitors by in Silico Virtual Screening”. Turkish Computational and Theoretical Chemistry 8, no. 2 (May 2024): 1-11. https://doi.org/10.33435/tcandtc.1224592.
EndNote Hasan Y, Al-hamashi A (May 1, 2024) Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Computational and Theoretical Chemistry 8 2 1–11.
IEEE Y. Hasan and A. Al-hamashi, “Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening”, Turkish Comp Theo Chem (TC&TC), vol. 8, no. 2, pp. 1–11, 2024, doi: 10.33435/tcandtc.1224592.
ISNAD Hasan, Yahya - Al-hamashi, Ayad. “Identification of Selisistat Derivatives As SIRT1-3 Inhibitors by in Silico Virtual Screening”. Turkish Computational and Theoretical Chemistry 8/2 (May 2024), 1-11. https://doi.org/10.33435/tcandtc.1224592.
JAMA Hasan Y, Al-hamashi A. Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Comp Theo Chem (TC&TC). 2024;8:1–11.
MLA Hasan, Yahya and Ayad Al-hamashi. “Identification of Selisistat Derivatives As SIRT1-3 Inhibitors by in Silico Virtual Screening”. Turkish Computational and Theoretical Chemistry, vol. 8, no. 2, 2024, pp. 1-11, doi:10.33435/tcandtc.1224592.
Vancouver Hasan Y, Al-hamashi A. Identification of Selisistat Derivatives as SIRT1-3 Inhibitors by in Silico Virtual Screening. Turkish Comp Theo Chem (TC&TC). 2024;8(2):1-11.

Journal Full Title: Turkish Computational and Theoretical Chemistry


Journal Abbreviated Title: Turkish Comp Theo Chem (TC&TC)