Novel Tgase2 Allosteric Site Inhibitors: A Computational Study

Year 2024, Volume: 8 Issue: 4, 83 - 92, 02.12.2024

Sude Sezgin , Gökhan Erdem Şahay , Nilhan Kızılkanat , Hüseyin Saygın Portakal

https://doi.org/10.33435/tcandtc.1441494

Abstract

Tranglutaminase-2 (Tgase2) is one of the primary Transglutaminase enzyme family members having a significant role in Ca2+ -dependent and -independent post-translational modifications. It has been previously reported that Tgase2 has significant regulatory roles over metabolic functions such as signaling pathways, inflammatory response, and wound healing. In particular, many cancer types’ prognosis includes over Tgase2 activity since it might induce metastasis through regulating crosslinking of extracellular matrix (ECM) proteins, and tumor proliferation via leading spheroid formation. Considering these fundamentals, discovery of novel chemical compounds to inhibit Tgase2 activity might be a strong approach in cancer treatment. Furthermore, it’s known that Tgase2 activity might be inhibited through blocking its allosteric site with chemical compounds. As such, a drug library including 12,111 small compounds were virtually screened to allosteric site of Tgase2. The study has been validated by repetition the strategy with previously discovered inhibitors. Allosteric and active sites of Tgase2 have been demonstrated with protein-protein docking technique. Eventually, recently discovered ligands have been characterized according to their ADME and toxicity profiles. Results have demonstrated that Eltrombopag, Talniflumate, and Lumacaftor drugs might be repurposed in the inhibition of Tgase2 since that they exhibit high binding affinity, ADME, and toxicity properties comparing the known inhibitors.

Keywords

Tgase2, Transglutaminase, Molecular Docking, Virtual Drug Screening, Protein-Protein Docking, ADME and Toxicity

References

• [1] S. Beninati, M. Piacentini, The transglutaminase family: An overview, Amino Acids 26 (2004) 367–372.
• [2] B. O. Odii, P. Coussons, Biological functionalities of transglutaminase 2 and the possibility of its compensation by other members of the transglutaminase family, Sci. World J. 2014 (2014) 7–9.
• [3] L. Lorand, S. E. Iismaa, Transglutaminase diseases: From biochemistry to the bedside, FASEB J. 33 (2019) 3–12.
• [4] G.E. Kim, H. H. Park, Structures of human transglutaminase 2: Finding clues for interference in cross-linking mediated activity, Int. J. Mol. Sci. 21 (2020) 35–38.
• [5] D. Park, S. S. Choi, and K. S. Ha, Transglutaminase 2: A multi-functional protein in multiple subcellular compartments, Amino Acids 39 (2010) 619–631.
• [6] L. Huang, A. M. Xu, and W. Liu, Transglutaminase 2 in cancer, Am. J. Cancer Res. 5 (2015) 2756–2776.
• [7] E. Kırmızıay, R. Demir, C. Öğütçü, and H. S. Portakal. Discovery of Repurposable Drugs in the Combination Therapy of Breast Cancer : A Virtual Drug Screening Study, Turkish Comp. Theo. Chem. 8 (2024) 40–53.
• [8] S. Kim, New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds, Med. Sci. 1 (2018) 1–11.
• [9] N. Kim et al., Allosteric inhibition site of transglutaminase 2 is unveiled in the N terminus, Amino Acids 50 (2018) 1583–1594.
• [10] E. F. Pettersen et al., UCSF Chimera — A Visualization System for Exploratory Research and Analysis, J. Comput. Chem. 25 (2004) 1605-1612.
• [11] S. Dallakyan, A. Olson, Small-Molecule Library Screening by Docking with PyRx, NY: Springer New York, U.S.A. 2015, 243-250.
• [12] O. Trott, A. J. Olson, AutoDock Vina : Improving the Speed and Accuracy of Docking with a New Scoring Function , Efficient Optimization , and Multithreading, J. Comput. Chem. 17 (2011) 295-304.
• [13] A. Porollo, J. Meller, Prediction-Based Fingerprints of Protein – Protein Interactions, Proteins 66 (2007) 630-645.
• [14] Y. Yan et al., HDOCK : a web server for protein – protein and protein – DNA / RNA docking based on a hybrid strategy, Nucleic Acids Res. 45 (2017) 365–373.
• [15] T. K. Karami et al., Eyes on Lipinski ’ s Rule of Five : A New ‘“ Rule of Thumb ”’ for Physicochemical Design Space of Ophthalmic Drugs, J. Ocul. Pharmacol. Ther. 38 (2022) 43–55.
• [16] A. Daina, O. Michielin, and V. Zoete, SwissADME: A free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules, Sci. Rep. 7 (2017) 1–13.
• [17] https://www.organic-chemistry.org/prog/peo/, January 2017, Accessed: 22.02.2024.
• [18] J. Jeon et al., GTP is required to stabilize and display transamidation activity of transglutaminase 2, Biochem. Biophys. Res. Commun. 294 (2002) 818–822.
• [19] B. Drexler, J. Passweg, Current evidence and the emerging role of eltrombopag in severe aplastic anemia, Ther. Adv. Hematol. 12 (2021) 1–10.
• [20] R. Desmond, D. M. Townsley, C. Dunbar, N. S. Young, Eltrombopag in aplastic anaemia, Semin. Hematol. 52 (2016) 31–37.
• [21] S. L. Corman, R. A. Mohammad, Eltrombopag: A Novel Oral Thrombopoietin Receptor Agonist, Ann. Pharmacother. 44 (2010) 1072–1079.
• [22] A. Agostini et al., Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab ‑ paclitaxel treatment in pancreatic cancer, J. Transl. Med. 21 (2023) 1–15.
• [23] N. M. Walker et al., Talniflumate Increases Survival in a Cystic Fibrosis Mouse Model of Distal Intestinal Obstructive Syndrome, J. Pharmacol. Exp. Ther. 317 (2006) 275–283.
• [24] D. M. Cholon et al., Efficacy of lumacaftor-ivacaftor for the treatment of cystic fibrosis patients homozygous for the F508del-CFTR mutation, Expert Rev. Precis. Med. Drug Dev. 1 (2016) 235-243.