Journal of Drug Design and Medicinal Chemistry

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Rational Computational Study for New Kinase Inhibitors

Received: Jun. 25, 2019    Accepted: Aug. 06, 2019    Published: Sep. 02, 2019
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Abstract

The development of new drugs can present several problems, it is a important obstacle the ability to adapt a molecule that is a potent pharmacological inhibitor and that is also possible to execute its synthesis. Quinazolines are known to be capable of inhibiting kinases. Thus, a detailed study was carried out to propose new quinazolines with already known synthetic routes, and that were promising for the ability to inhibit kinases. A drug candidate molecule shall be proposed to have a good absorption, an extensive distribution so it’s capable of reaching the desired therapeutic targets. Lipinski's Rule of 5 in computational studies has been applied to select more promising molecules. In this study, the molecules proposed for the synthesis were systematically designed in appropriate computational programs to test several substituents of the quinazoline nucleus on the capacity of these molecules to be considered inhibitors of kinases. Six molecules were selected with the best results to inhibit kinases. In the study to evaluate the variation of substituents, the result obtained for the 8-position of the quinazoline ring and with the -Cl substituent at that ring position presented 60% of the 10 best molecules capable of inhibiting kinases. The molecular docking study confirmed that the two most promising molecules to inhibit kinase also obtained the best results to inhibit AKT kinase. Therefore, through this study it was possible to select six more promising molecules to be synthesized and available in large screening tests for several therapeutic targets known as High-Throughput Screening.

DOI 10.11648/j.jddmc.20190503.12
Published in Journal of Drug Design and Medicinal Chemistry ( Volume 5, Issue 3, September 2019 )

This article belongs to the Special Issue Drug Discovery of New Kinases Inhibitors

Page(s) 40-46
Creative Commons

This is an Open Access article, distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium or format, provided the original work is properly cited.

Copyright

Copyright © The Author(s), 2024. Published by Science Publishing Group

Keywords

Kinase Inhibitor, Quinazoline, Molecular Docking

References
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[3] http://www.molinspiration.com access in 25/04/2019.
[4] Fernandes, G. S.; Pereira, M. B. M.; Freitas, M. P.; Antunes, J. E. Open Journal of Medicinal Chemistry, 2015, 5, 106-115.
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[8] Tobe, M.; Isobe, Y.; Tomizawa, H.; Nagasaki, T.; Takahashi, H.; Fukazawa, T.; Hayashi, H.. Bioorg. & Med. Chem. 2003, 11: 383–391.
[9] ACD ChemSketch versão 8.17, 2005. www.acdlabs.com/products/draw_nom/draw.
[10] Lipinski, C. A.; Lombardo, F.; Dominy, B. W.; Feeney, P. J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development setting. Adv. Drug Deliv. Rev. 1997, 23:3-25.
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[13] Lipinski, C. A. Drug-Like Proprerties and the Causes of Poor Solubility and Poor Permeability, J. Pharmacol. Toxicol. Methods. 2000, 44: 235-249.
[14] Fernandes, G. S.; Pereira, M. B. M.; dos Santos, G. R. R. M.; Antunes, J. E. New method for predict biological activity of kinases inhibitors, SCIREA Journal of Chemistry, V2, Issue 2, 2017.
[15] Golan, D. E.; Tashjian, A. H.; Jr.; Armstrong, E. J. April W. Armstrong, A. W. Principle of Pharmacology, 2a ed. 2009, Willians & Wilkins,. Cap. 1.
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    Joao Eustaquio Antunes, Michelle Bueno de Moura Pereira. (2019). Rational Computational Study for New Kinase Inhibitors. Journal of Drug Design and Medicinal Chemistry, 5(3), 40-46. https://doi.org/10.11648/j.jddmc.20190503.12

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    ACS Style

    Joao Eustaquio Antunes; Michelle Bueno de Moura Pereira. Rational Computational Study for New Kinase Inhibitors. J. Drug Des. Med. Chem. 2019, 5(3), 40-46. doi: 10.11648/j.jddmc.20190503.12

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    AMA Style

    Joao Eustaquio Antunes, Michelle Bueno de Moura Pereira. Rational Computational Study for New Kinase Inhibitors. J Drug Des Med Chem. 2019;5(3):40-46. doi: 10.11648/j.jddmc.20190503.12

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  • @article{10.11648/j.jddmc.20190503.12,
      author = {Joao Eustaquio Antunes and Michelle Bueno de Moura Pereira},
      title = {Rational Computational Study for New Kinase Inhibitors},
      journal = {Journal of Drug Design and Medicinal Chemistry},
      volume = {5},
      number = {3},
      pages = {40-46},
      doi = {10.11648/j.jddmc.20190503.12},
      url = {https://doi.org/10.11648/j.jddmc.20190503.12},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.jddmc.20190503.12},
      abstract = {The development of new drugs can present several problems, it is a important obstacle the ability to adapt a molecule that is a potent pharmacological inhibitor and that is also possible to execute its synthesis. Quinazolines are known to be capable of inhibiting kinases. Thus, a detailed study was carried out to propose new quinazolines with already known synthetic routes, and that were promising for the ability to inhibit kinases. A drug candidate molecule shall be proposed to have a good absorption, an extensive distribution so it’s capable of reaching the desired therapeutic targets. Lipinski's Rule of 5 in computational studies has been applied to select more promising molecules. In this study, the molecules proposed for the synthesis were systematically designed in appropriate computational programs to test several substituents of the quinazoline nucleus on the capacity of these molecules to be considered inhibitors of kinases. Six molecules were selected with the best results to inhibit kinases. In the study to evaluate the variation of substituents, the result obtained for the 8-position of the quinazoline ring and with the -Cl substituent at that ring position presented 60% of the 10 best molecules capable of inhibiting kinases. The molecular docking study confirmed that the two most promising molecules to inhibit kinase also obtained the best results to inhibit AKT kinase. Therefore, through this study it was possible to select six more promising molecules to be synthesized and available in large screening tests for several therapeutic targets known as High-Throughput Screening.},
     year = {2019}
    }
    

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    T2  - Journal of Drug Design and Medicinal Chemistry
    JF  - Journal of Drug Design and Medicinal Chemistry
    JO  - Journal of Drug Design and Medicinal Chemistry
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    PB  - Science Publishing Group
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    UR  - https://doi.org/10.11648/j.jddmc.20190503.12
    AB  - The development of new drugs can present several problems, it is a important obstacle the ability to adapt a molecule that is a potent pharmacological inhibitor and that is also possible to execute its synthesis. Quinazolines are known to be capable of inhibiting kinases. Thus, a detailed study was carried out to propose new quinazolines with already known synthetic routes, and that were promising for the ability to inhibit kinases. A drug candidate molecule shall be proposed to have a good absorption, an extensive distribution so it’s capable of reaching the desired therapeutic targets. Lipinski's Rule of 5 in computational studies has been applied to select more promising molecules. In this study, the molecules proposed for the synthesis were systematically designed in appropriate computational programs to test several substituents of the quinazoline nucleus on the capacity of these molecules to be considered inhibitors of kinases. Six molecules were selected with the best results to inhibit kinases. In the study to evaluate the variation of substituents, the result obtained for the 8-position of the quinazoline ring and with the -Cl substituent at that ring position presented 60% of the 10 best molecules capable of inhibiting kinases. The molecular docking study confirmed that the two most promising molecules to inhibit kinase also obtained the best results to inhibit AKT kinase. Therefore, through this study it was possible to select six more promising molecules to be synthesized and available in large screening tests for several therapeutic targets known as High-Throughput Screening.
    VL  - 5
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Author Information
  • Department of Pharmacy, Federal University of Juiz de Fora, Governador Valadares, Brazil

  • Department of Life Basic Sciences, Federal University of Juiz de Fora, Governador Valadares, Brazil

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