Journal of Drug Design and Medicinal Chemistry

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Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach

Received: Sep. 24, 2018    Accepted: Oct. 08, 2018    Published: Nov. 05, 2018
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Abstract

The SHP2 protein is a Protein tyrosine phosphates (PTPs) protein family, it catalyze the dephosphorylation of phosphotyrosine residues in protein substrates and play a critical roles in regulating intracellular signal transduction and is responsible for controlling cell growth, differentiation, motility, and metabolism. Whereas, Shp2 has non-receptor PTP containing two N-terminal Src homology 2 (SH2) domains, a PTP domain, and a C-terminal tail. The SHP2 adopts an auto-inhibited conformation in its basal state, whereby the N-terminal SH2 domain interacts with the PTP domain and blocks access to the catalytic site. The phosphorylated proteins bind to the SH2 domains of SHP2 and activate the dephosphorylation, which imparts down regulation of RTK-dependent signaling leads to activate oncogenes. Hence, The Shp2-PTPs interaction in physiological processes and that modulation of their enzymatic activity may constitute a therapeutic approach for the treatment of cancer. In the present work we have designed the four sulpho tyrosine based unnatural amino acid libraries through the Insilico modeling, to demonstrate the utility of, Phenyl sulfoaceticacid (PSAA) based Cap-group (a novel sulpho-Tyrosine Mimic) incorporated with novel N-heterocyclic based unnatural amino acid as a Spacer in Library-1, n-Dioxothiazolidene spacer in Library-2, n-pyridazine spacer in library-3 and n-imidazole spacer in library-4 respectively, which was development for novel anti cancerous Shp2- inhibitors, resulted in the five most potential ligand such as Ligand-1a &1b, 2a, 4a & 4b has shown to significant anti-cancerous shp2 inhibitor activity when compared with standard ligand SHP099.

DOI 10.11648/j.jddmc.20180403.11
Published in Journal of Drug Design and Medicinal Chemistry ( Volume 4, Issue 3, September 2018 )
Page(s) 22-34
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

SHP2, Protein Tyrosine Phosphatases, Sulpho Tyrosine, Unnatural Amino Acid and Docking

References
[1] Zeng, L. F.; Zhang, R. Y.; Yu, Z. H.; Li, S.; Wu, L.; Gunawan, A. M.; Lane, B. S.; Mali, R. S.; Li, X.; Chan, R. J.; Kapur, R.; Wells, C. D.; Zhang, Z. Y. Therapeutic Potential of Targeting the Oncogenic SHP2 Phosphatase. J. Med. Chem. (2014), 57, 6594–6609.
[2] Butterworth, S.; Overduin, M.; Barr, A. J. Targeting protein tyrosine phosphatase SHP2 for therapeutic intervention. Future Med. Chem. (2014), 6, 1423−1437.
[3] Zhang X, He Y, Liu S, et al. Salicylic acid based small molecule inhibitor for the oncogenic Src homology-2 domain containing protein tyrosine phosphatase-2 (SHP2). J Med Chem. (2010), 53 (6):2482-2493.
[4] Jingyan Ge, a Hao Wub and Shao Q. Yao, An unnatural amino acid that mimics phosphotyrosine., Chem Comm., (2010).3., 1-3.
[5] Rongjun He, Zhi-Hong Yu, Ruo-Yu Zhang, Li Wu, Andrea M. Gunawan, Brandon S. Lane, Joong S. Shim, Li-Fan Zeng, Yantao He, Lan Chen, Clark D. Wells, Jun O. Liu, and Zhong-Yin Zhang, Exploring the Existing Drug Space for Novel pTyr Mimetic and SHP2 Inhibitors., ACS Med. Chem. Lett. (2015), 6, 782−786.
[6] Chan, G.; Kalaitzidis, D.; Neel, B. G. The Tyrosine Phosphatase Shp2 (PTPN11) in Cancer. Cancer Metastasis Rev. (2008), 27, 179–192.
[7] Fortanet, J. G.; Chen, C. H–T; Chen, Y. P.; Chen, Z.; Deng, Z.; Firestone, B.; Fekkes, P.; Fodor, M; Fortin, P. D.; Fridrich, C.; Grunenfelder, D.; Ho, S.; Kang, Z. B.; Karki, R.; Kato, M.; Keen, N.; LaBonte, L. R.; Larrow, J.; Lenoir, F.; Liu, G.; Liu, S.; Lombardo, F.; Majumdar, D.; Meyer, M. J.; Palermo, M.; Perez, L. B.; Pu, M.; Ramsey, T.; Sellers, W. R.; Shultz, M. D.; Stams, T.; Towler, C. S.; Wang, P.; Williams, S. L.; Zhang, J.–H.; LaMarche, M. J.; Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor. J. Med. Chem., (2016), 59, 7773–7782.
[8] Vogel W, Lammers R, Huang J, Ullrich A. Activation of a phosphotyrosine phosphatase by tyrosine phosphorylation. Science. (1993), 259 (5101) 1611-1614.
[9] McPherson VA, Sharma N, Everingham S, et al. SH2 domain-containing phosphatase-2 proteintyrosine phosphatase promotes Fc epsilon RI-induced activation of Fyn and Erk pathways leading to TNF alpha release from bone marrowderived mast cells. J Immunol. (2009), 183 (8):4940-4947.
[10] Zhang EE, Chapeau E, Hagihara K, Feng GS. Neuronal Shp2 tyrosine phosphatase controls energy balance and metabolism. Proc Natl Acad Sci U S A. (2004), 101 (45):16064-16069.
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    Rajaganapathy Kaliyaperumal, Manjunatha Panduranga Mudugal, Prashantha Nagaraja, Nageena Taj. (2018). Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach. Journal of Drug Design and Medicinal Chemistry, 4(3), 22-34. https://doi.org/10.11648/j.jddmc.20180403.11

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    ACS Style

    Rajaganapathy Kaliyaperumal; Manjunatha Panduranga Mudugal; Prashantha Nagaraja; Nageena Taj. Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach. J. Drug Des. Med. Chem. 2018, 4(3), 22-34. doi: 10.11648/j.jddmc.20180403.11

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    AMA Style

    Rajaganapathy Kaliyaperumal, Manjunatha Panduranga Mudugal, Prashantha Nagaraja, Nageena Taj. Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach. J Drug Des Med Chem. 2018;4(3):22-34. doi: 10.11648/j.jddmc.20180403.11

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  • @article{10.11648/j.jddmc.20180403.11,
      author = {Rajaganapathy Kaliyaperumal and Manjunatha Panduranga Mudugal and Prashantha Nagaraja and Nageena Taj},
      title = {Exploration of Novel Sulpho Tyrosine Based Unnatural Amino Acid Ligand for Inhibition of Human Shp2; A Computational Approach},
      journal = {Journal of Drug Design and Medicinal Chemistry},
      volume = {4},
      number = {3},
      pages = {22-34},
      doi = {10.11648/j.jddmc.20180403.11},
      url = {https://doi.org/10.11648/j.jddmc.20180403.11},
      eprint = {https://download.sciencepg.com/pdf/10.11648.j.jddmc.20180403.11},
      abstract = {The SHP2 protein is a Protein tyrosine phosphates (PTPs) protein family, it catalyze the dephosphorylation of phosphotyrosine residues in protein substrates and play a critical roles in regulating intracellular signal transduction and is responsible for controlling cell growth, differentiation, motility, and metabolism. Whereas, Shp2 has non-receptor PTP containing two N-terminal Src homology 2 (SH2) domains, a PTP domain, and a C-terminal tail. The SHP2 adopts an auto-inhibited conformation in its basal state, whereby the N-terminal SH2 domain interacts with the PTP domain and blocks access to the catalytic site. The phosphorylated proteins bind to the SH2 domains of SHP2 and activate the dephosphorylation, which imparts down regulation of RTK-dependent signaling leads to activate oncogenes. Hence, The Shp2-PTPs interaction in physiological processes and that modulation of their enzymatic activity may constitute a therapeutic approach for the treatment of cancer. In the present work we have designed the four sulpho tyrosine based unnatural amino acid libraries through the Insilico modeling, to demonstrate the utility of, Phenyl sulfoaceticacid (PSAA) based Cap-group (a novel sulpho-Tyrosine Mimic) incorporated with novel N-heterocyclic based unnatural amino acid as a Spacer in Library-1, n-Dioxothiazolidene spacer in Library-2, n-pyridazine spacer in library-3 and n-imidazole spacer in library-4 respectively, which was development for novel anti cancerous Shp2- inhibitors, resulted in the five most potential ligand such as Ligand-1a &1b, 2a, 4a & 4b has shown to significant anti-cancerous shp2 inhibitor activity when compared with standard ligand SHP099.},
     year = {2018}
    }
    

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    AU  - Rajaganapathy Kaliyaperumal
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    JO  - Journal of Drug Design and Medicinal Chemistry
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    UR  - https://doi.org/10.11648/j.jddmc.20180403.11
    AB  - The SHP2 protein is a Protein tyrosine phosphates (PTPs) protein family, it catalyze the dephosphorylation of phosphotyrosine residues in protein substrates and play a critical roles in regulating intracellular signal transduction and is responsible for controlling cell growth, differentiation, motility, and metabolism. Whereas, Shp2 has non-receptor PTP containing two N-terminal Src homology 2 (SH2) domains, a PTP domain, and a C-terminal tail. The SHP2 adopts an auto-inhibited conformation in its basal state, whereby the N-terminal SH2 domain interacts with the PTP domain and blocks access to the catalytic site. The phosphorylated proteins bind to the SH2 domains of SHP2 and activate the dephosphorylation, which imparts down regulation of RTK-dependent signaling leads to activate oncogenes. Hence, The Shp2-PTPs interaction in physiological processes and that modulation of their enzymatic activity may constitute a therapeutic approach for the treatment of cancer. In the present work we have designed the four sulpho tyrosine based unnatural amino acid libraries through the Insilico modeling, to demonstrate the utility of, Phenyl sulfoaceticacid (PSAA) based Cap-group (a novel sulpho-Tyrosine Mimic) incorporated with novel N-heterocyclic based unnatural amino acid as a Spacer in Library-1, n-Dioxothiazolidene spacer in Library-2, n-pyridazine spacer in library-3 and n-imidazole spacer in library-4 respectively, which was development for novel anti cancerous Shp2- inhibitors, resulted in the five most potential ligand such as Ligand-1a &1b, 2a, 4a & 4b has shown to significant anti-cancerous shp2 inhibitor activity when compared with standard ligand SHP099.
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Author Information
  • Department of Pharmacology, Acharya & BM Reddy College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, India

  • Department of Pharmacology, Acharya & BM Reddy College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, India

  • Department of Biotechnology, School of Chemical and Biological Sciences, REVA University, Bengaluru, India

  • Department of Pharmacology, Acharya & BM Reddy College of Pharmacy, Rajiv Gandhi University of Health Sciences, Bengaluru, India

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