Novel Tgase2 Allosteric Site Inhibitors: A Computational Study

Yıl 2024, Cilt: 8 Sayı: 4, 83 - 92

Sude Sezgin Gökhan Erdem Şahay Nilhan Kızılkanat Hüseyin Saygın Portakal

Öz

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.

Anahtar Kelimeler

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

Kaynakça

• [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.