Screening and Development of Transglutaminase-2 Inhibitors and their Derivative as Anti-lung Cancer Agent by in silico and in vitro Approaches

• Published in: Current computer-aided drug design Vol. 18; no. 1; p. 41
• Main Authors: Parvatikar, Prachi P, Patil, Sumangala, Hoskeri, Joy, Swargam, Sandeep, Kulkarni, Raghvendra V, Das, Kusal K
• Format: Journal Article
• Language: English
• Published: United Arab Emirates 01.01.2022
• Subjects: A549 Cells; Early Detection of Cancer; Enzyme Inhibitors - pharmacology; Humans; Lung Neoplasms - drug therapy; Molecular Docking Simulation; Protein Glutamine gamma Glutamyltransferase 2 - antagonists & inhibitors; lung cancer; molecular docking; molecular interaction; cystamine derivative; simulation; TG2
• ISSN: 1875-6697
• DOI: 10.2174/1573409917666210322120350

This study aimed at screening and development of TG2 inhibitors as anti lung cancer agent. Transglutaminase 2 (TG2) is multifunctional and ubiquitously expressed protein from the transglutaminase family. It takes part in various cellular processes and plays an important role in the pathogenesis of autoimmune, neurodegerative diseases, and also cancer. The proposed study focused on screening potent inhibitors of TG2 by in-silico method and synthesize their derivative as well as analyse its activity by utilizing an in-vitro approach. Molecular docking studies have been carried out on the different classes of TG2 inhibitors against the target protein. Nearly thirty TG2 inhibitors were selected from literature and docking was performed against transglutaminase 2. The computational ADME property screening was also carried out to check their pharmacokinetic properties. The compounds which exhibited positive ADME properties with good interaction while possessing the least binding energy were further validated for their anti-lung cancer inhibition property against A549 cell lines using cytotoxicity studies. The results of the present study indicate that the docked complex formed by cystamine showed better binding affinity towards target protein, so this derivative of cystamine was formed using 2,5 dihydrobenzoic acid. Invitro results revealed that both molecules proved to be good cytotoxic agents against A549 lung cancer (875.10, 553.22 μg/ml), respectively. Further, their activity needs to be validated on TG2 expressing lung cancer. Cystamine and its derivative can act as a potential therapeutic target for lung cancer but its activity should be further validated on TG2 expressing lung cancer.