In silico; Linoleic acid and palmitic acid exerts antidiabetic effects by inhibiting protein tyrosine phosphatases associated with insulin resistance

Main Article Content

Maha H.Al-Bahrani
Nada A.Kadhim
Raghad S. Mouhamad
Khlood Abedalelah Al-Khafaji


Inhibiting protein tyrosine phosphatases, Diabetes, Phytochemical, Phytomedicine, Drug development.


Objectives: The search for potential bioactive compounds for the discovery and development of targeted novel antidiabetic drugs is becoming more and more popular among scientists. So, the aim of this research is to find the inhibition activity of palmitic acid and linoleic acid extracted from Ballota saxatilis against protein tyrosine phosphatase (PTP: B1, N9 and 11) through simulation using molecular docking.

Methods: Gas chromatography technique (GC) (Chrompack-Packard 438A) and a separation column type 30-SE with an inner diameter of 0.25 mm and a length of 30 m, was used to describe the biologically active chemicals found in Ballota saxatilis extracts.

Results: Simulation technique gave the binding affinity, hydrogen bonding and the distances between ligand and its corresponding enzyme molecule. Molecular docking revealed that palmitic acid had strong binding affinities for PTP1B (-7.8) and PTP9 (-7.9) but had weaker affinities for PTP11 (up to (-7.4). α- Linoleic Acid (ALA) produced closely results of binding activity against PTP1B (-6.2) and PTP9 (-6.1) and lower binding activity reacted with PTP11. However, the ligand α- Linoleic acid could form hydrogen bonding beside other interactions with PTP1B, PTPN9 and PTPN11. The other ligand palmitic acid formed mainly hydrophobic interactions with the three enzymes. Only one hydrogen bond existed between ligand palmitic acid and the amino acid Lys260 located at PTPN11

Conclusions: The extract of herb B. saxitalis could be applied by the researchers, and pharmaceutical companies around the world for inhibition of PTP1B, PTPN9 and PTPN11. These compounds may control diabetes with fewer side effects than conventional antidiabetic medications.

Abstract 216 | pdf Downloads 79 PDF Downloads 260 XML Downloads 109 HTML Downloads 18


1. Villamar-Cruz O, Loza-Mejía MA, Arias-Romero LE, Camacho-Arroyo I. Recent advances in PTP1B signaling in metabolism and cancer. Biosci Rep. 2021 Nov 26;41(11):BSR20211994.
2. Singh, S., Singh Grewal, A., Grover, R., Sharma, N., Chopra, B., Kumar Dhingra, A., Arora, S., Redhu, S., & Lather, V. Recent updates on development of protein-tyrosine phosphatase 1B inhibitors for treatment of diabetes, obesity and related disorders. Bioorganic chemistry 2022; 121: 105626.
3. Long YC, Zierath JR. AMP-activated protein kinase signaling in metabolic regulation. J Clin Invest. 2006 Jul;116 (7):1776-83.
4. Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. AMPK activation: a therapeutic target for type 2 diabetes? Diabetes Metab Syndr Obes 2014 Jun 24; 7:241-53.
5. Liu R, Mathieu C, Berthelet J, Zhang W, Dupret J-M, Rodrigues Lima F. Human Protein Tyrosine Phosphatase 1B (PTP1B): From Structure to Clinical Inhibitor Perspectives. International Journal of Molecular Sciences 2022; 23(13):7027.
6. Ranjithmenon Muraleedharan, Biplab Dasgupta, AMPK in the brain: its roles in glucose and neural metabolism, The FEBS Journal, 10.1111/febs 2021; 16151, 289, 8: 2247-2262.
7. Zinker, B. A., Rondinone, C. M., Trevillyan, J. M., Gum, R. J., Clampit, J. E., Waring, J. F., Xie, N., Wilcox, D., Jacobson, P., Frost, L., Kroeger, P. E., Reilly, R. M., Koterski, S., Opgenorth, T. J., Ulrich, R. G., Crosby, S., Butler, M., Murray, S. F., McKay, R. A., Bhanot, S., Jirousek, M. R. PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proceedings of the National Academy of Sciences of the United States of America 2002; 99(17): 11357–11362.
8. Aberdein N, Dambrino RJ, do Carmo JM, Wang Z, Mitchell LE, Drummond HA, Hall JE. Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance. Am J Physiol Regul Integr Comp Physiol 2018; Mar 1; 314(3):R478-R488.
9. Abdelsalam SS, Korashy HM, Zeidan A, Agouni A. The Role of Protein Tyrosine Phosphatase (PTP)-1B in Cardiovascular Disease and Its Interplay with Insulin Resistance. Biomolecules 2019 Jul 17;9(7):286.
10. Dubé N, Cheng A, Tremblay ML. The role of protein tyrosine phosphatase 1B in Ras signaling. Proc Natl Acad Sci U S A 2004 Feb 17; 101(7):1834-9.
11. Kumar, A., Rana, D., Rana, R., & Bhatia, R. Protein Tyrosine Phosphatase (PTP1B): A promising Drug Target Against Life-threatening Ailments. Current molecular pharmacology 2020 ; 13(1), 17–30.
12. Desjarlais M, Ruknudin P, Wirth M, Lahaie I, Dabouz R, Rivera JC, Habelrih T, Omri S, Hardy P, Rivard A, Chemtob S. Tyrosine-Protein Phosphatase Non-receptor Type 9 (PTPN9) Negatively Regulates the Paracrine Vasoprotective Activity of Bone-Marrow Derived Pro-angiogenic Cells: Impact on Vascular Degeneration in Oxygen-Induced Retinopathy. Front Cell Dev Biol. 2021 May 28;9: 679906.
13. Yoon SY, Yu JS, Hwang JY, So HM, Seo SO, Kim JK, Jang TS, Chung SJ, Kim KH. Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance. Molecules. 2021 Mar 14; 26(6):1612.
14. Oh YS, Bae GD, Baek DJ, Park EY, Jun HS. Fatty Acid-Induced Lipotoxicity in Pancreatic Beta-Cells During Development of Type 2 Diabetes. Front Endocrinol (Lausanne). 2018 Jul 16; 9:384.
15. Drożdż K, Nabrdalik K, Hajzler W, Kwiendacz H, Gumprecht J, Lip GYH. Metabolic-Associated Fatty Liver Disease (MAFLD), Diabetes, and Cardiovascular Disease: Associations with Fructose Metabolism and Gut Microbiota. Nutrients. 2021 Dec 27; 14(1):103.
16. Tsuda N, Kawaji A, Sato T, Takagi M, Higashi C, Kato Y, Ogawa K, Naba H, Ohkouchi M, Nakamura M, Hosaka Y, Sakaki J. A novel free fatty acid receptor 1 (GPR40/FFAR1) agonist, MR1704, enhances glucose-dependent insulin secretion and improves glucose homeostasis in rats. Pharmacol Res Perspect. 2017 Aug; 5(4):e00340.
17. Fridlyand LE, Philipson LH. Pancreatic Beta Cell G-Protein Coupled Receptors and Second Messenger Interactions: A Systems Biology Computational Analysis. PLoS One. 2016 May 3;11 (5):e0152869.
18. Kalis M, Levéen P, Lyssenko V, Almgren P, Groop L, Cilio CM. Variants in the FFAR1 gene are associated with beta cell function. PLoS One. 2007 Nov 7;2(11):e1090.
19. Park MH, Kim DH, Lee EK, Kim ND, Im DS, Lee J, Yu BP, Chung HY. Age-related inflammation and insulin resistance: a review of their intricate interdependency. Arch Pharm Res. 2014 Dec;37(12):1507-14.
20. Roberts CK, Hevener AL, Barnard RJ. Metabolic syndrome and insulin resistance: underlying causes and modification by exercise training. Compr Physiol. 2013 Jan;3(1):1-58.
21. Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: dietary components and nutritional strategies. Lancet. 2014 Jun 7;383(9933):1999-2007.
22. Salas-Salvadó, J., Martinez-González, M. Á., Bulló, M., & Ros, E. The role of diet in the prevention of type 2 diabetes. Nutrition, metabolism, and cardiovascular diseases: NMCD (2011); 21 Suppl 2, B32–B48.
23. Ghaedi N, Pouraboli I, Askari N. Antidiabetic Properties of Hydroalcoholic Leaf and Stem Extract of Levisticum officinale: An implication for α-amylase Inhibitory Activity of Extract Ingredients through Molecular Docking. Iran J Pharm Res. 2020 Winter;19(1):231-250.
24. Abdullah, M., Al-Khafaji, K., Mouhamad, R., & Hussein, R. In-vivo study of the anti-diabetic effect of Ballota saxatilis. DYSONA - Life Science 2020; 1(2), 70-75.
25. Azadbakht L, Rouhani MH, Surkan PJ. Omega-3 fatty acids, insulin resistance and type 2 diabetes. J Res Med Sci. 2011 Oct;16 (10):1259-60.
26. Jiang, Cs., Liang, Lf. & Guo, Yw. Natural products possessing protein tyrosine phosphatase 1B (PTP1B) inhibitory activity found in the last decades. Acta Pharmacol Sin. 2012; 33, 1217–1245.
27. Dass AS, Narayana S, Venkatarathnamma PN. Effect of Vitamin E and omega 3 fatty acids in type 2 diabetes mellitus patients. J Adv Pharm Technol Res. 2018 Jan-Mar;9(1):32-36.
28. Jovanovski E, Li D, Thanh Ho HV, Djedovic V, Ruiz Marques AC, Shishtar E, Mejia SB, Sievenpiper JL, de Souza RJ, Duvnjak L, Vuksan V. The effect of alpha-linolenic acid on glycemic control in individuals with type 2 diabetes: A systematic review and meta-analysis of randomized controlled clinical trials. Medicine (Baltimore). 2017 May; 96(21):e6531.
29. Sharma, C., Kim, Y., Ahn, D. et al. Protein tyrosine phosphatases (PTPs) in diabetes: causes and therapeutic opportunities. Arch. Pharm. Res. 2021; 44, 310–321.
30. Ruddraraju KV, Zhang ZY. Covalent inhibition of protein tyrosine phosphatases. Mol Biosyst. 2017 Jun 27;13 (7):1257-1279.
31. Yue X, Han T, Hao W, Wang M, Fu Y. SHP2 knockdown ameliorates liver insulin resistance by activating IRS-2 phosphorylation through the AKT and ERK1/2 signaling pathways. FEBS Open Bio. 2020 Dec;10(12):2578-2587.
32. Saini V. Molecular mechanisms of insulin resistance in type 2 diabetes mellitus. World J Diabetes. 2010 Jul 15;1(3):68-75.
33. Paschoal VA, Walenta E, Talukdar S, Pessentheiner AR, Osborn O, Hah N, et al. Positive Reinforcing Mechanisms Between GPR120 and Pparγ Modulate Insulin Sensitivity. Cell Metab. 2020; 31(6):1173–88.e5.