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Transglutaminase 2 (TG2) is a calcium-dependent enzyme that catalyzes the N-ϵ-(γ-glutamyl) lysine bonds between side chains of glutamine and lysine residues resulting in proteolytically resistant cross-links. Increased TG2 activity and levels are involved in the pathophysiology of various diseases, including liver injury, cystic fibrosis, celiac sprue, metastatic cancers, and several neurodegenerative conditions. Inhibiting TG2 activity is considered a potential strategy to combat these diseases. Although guanine nucleotide (GTP) could inhibit TG2, its inhibitory activity decreased with increased calcium concentration. Search for GTP analogs that could strongly bind and inhibit TG2 activity is intense. This study screened the PubChem database for about two thousand GTP-like compounds for TG2. Using docking and molecular dynamics simulations we identified three compounds (C4959, C4215, and C9560) that could selectively interact with TG2. These three compounds have less affinity for several other intracellular and extracellular GTP-binding proteins suggesting selectivity for TG2. Interestingly, C9560 showed stronger interactions and better binding energy with TG2 than C4959 and C4215, suggesting that C9560 can form a more stable complex with TG2. Our study indicates that C9560, a GTP analog, could be exploited as a promising candidate to inhibit TG2-mediated fibrotic conditions.

Identification of Novel GTP Analogs as Potent and Specific Reversible Inhibitors for Transglutaminase 2