Rational Computational Study for New Kinase Inhibitors

Joao Eustaquio Antunes; Michelle Bueno de Moura Pereira

doi:doi:10.11648/j.jddmc.20190503.12

| Peer-Reviewed

Rational Computational Study for New Kinase Inhibitors

Joao Eustaquio Antunes, Michelle Bueno de Moura Pereira

Published in Journal of Drug Design and Medicinal Chemistry (Volume 5, Issue 3)

Received: 25 June 2019 Accepted: 6 August 2019 Published: 2 September 2019

Views: Downloads:

Download PDF

Share This Article

Twitter
Linked In
Facebook

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.

Published in	Journal of Drug Design and Medicinal Chemistry (Volume 5, Issue 3) This article belongs to the Special Issue Drug Discovery of New Kinases Inhibitors
DOI	10.11648/j.jddmc.20190503.12
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), 2019. Published by Science Publishing Group

Keywords

Kinase Inhibitor, Quinazoline, Molecular Docking

References

[1]	David E. Golan, Armen H. Tashjian, Jr., Ehrin J. Armstrong, April W. Aemstrong, Principle of Pharmacology, 2^ª ed. 2008, Willians & Wilkins. 3-7.
[2]	Barreiro, E. J. As Bases Moleculares da Ação dos Fármacos, Fraga, C. A. M 2^ª ed.; Porto Alegre, 2008, P.41.
[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.
[5]	Thomas, G. In Computer Aided Drug. Fund. Med. Chem. 2003, 98-109.
[6]	Levitzki, A.; Mishani E. Annual Review Biochemistry 2006, 75, 93.
[7]	Connolly, D. J.; Cusack, D.; O´Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
[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.
[11]	https://www.rcsb.org/ access in 02/05/2019.
[12]	Thomsen, R.; Christensen, M. H.; MolDock: A new technique for high-accuracy molecular docking. Journ. Med. Chem. 2006, 49: 3315-21.
[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.
[16]	Wu P, Nielsen TE, Clausen MH. Drug Discov Today. 2015 Jul; 36 (7):422-39.
[17]	Al‐Damluji, S.; Kopin, I. J. Br. Journal of Pharmacology 1998, 124, 693.
[18]	Murer B. Targeted therapy in non-small cell lung cancer: a commentary. Arch Path Lab Med 2008; (132):1573-1575.

Cite This Article

Plain Text BibTeX RIS

APA Style

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

Copy | Download

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

Copy | Download

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

Copy | Download

@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://article.sciencepublishinggroup.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}
}

Copy | Download

TY  - JOUR
T1  - Rational Computational Study for New Kinase Inhibitors
AU  - Joao Eustaquio Antunes
AU  - Michelle Bueno de Moura Pereira
Y1  - 2019/09/02
PY  - 2019
N1  - https://doi.org/10.11648/j.jddmc.20190503.12
DO  - 10.11648/j.jddmc.20190503.12
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 40
EP  - 46
PB  - Science Publishing Group
SN  - 2472-3576
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
IS  - 3
ER  -

Copy | Download

Author Information

Joao Eustaquio Antunes

Department of Pharmacy, Federal University of Juiz de Fora, Governador Valadares, Brazil
Michelle Bueno de Moura Pereira

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

Download PDF

Sections

Plain Text BibTeX RIS

APA Style

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

Copy | Download

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

Copy | Download

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

Copy | Download

@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://article.sciencepublishinggroup.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}
}

Copy | Download

TY  - JOUR
T1  - Rational Computational Study for New Kinase Inhibitors
AU  - Joao Eustaquio Antunes
AU  - Michelle Bueno de Moura Pereira
Y1  - 2019/09/02
PY  - 2019
N1  - https://doi.org/10.11648/j.jddmc.20190503.12
DO  - 10.11648/j.jddmc.20190503.12
T2  - Journal of Drug Design and Medicinal Chemistry
JF  - Journal of Drug Design and Medicinal Chemistry
JO  - Journal of Drug Design and Medicinal Chemistry
SP  - 40
EP  - 46
PB  - Science Publishing Group
SN  - 2472-3576
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
IS  - 3
ER  -

Copy | Download