tTG2 library

            Celiac disease is a chronic autoimmune disorder that is common worldwide (affecting 1.4% of the population [1]). Despite its prevalence, there are no FDA-approved celiac disease medical treatments. Human tissue transglutaminase (tTG) is a protein that plays a key role in the molecular mechanism of the disease [2]. Currently tTG is one of the most promising targets for developing celiac disease medications.

            Modern tTG inhibitors are categorized into competitive amine inhibitors, reversible and irreversible inhibitors [3]. Among the tTG inhibitors, peptidomimetic irreversible inhibitors have achieved significant strides, with one of their representatives, ZED1227, successfully completing Phase 2a clinical trials for celiac disease, thus demonstrating its safety and validating tTG as a viable drug target [4]. However, the potential of small molecules as successful alternatives to the peptidomimetic inhibitors [5] as drug molecules targeting tissue transglutaminase has not been explored in full.

            We assembled a library of potential tTG inhibitors using as a seed a combination of known ChEMBL tTG ligands, which were expanded in several iterations, using chemoinformatics techniques and molecular docking, thus expanding the chemical space of reversible tTG ligands. The resulting molecules were grouped into the medicinal chemistry forming series with reasonable diversity within each group, thus facilitating hit-to-lead transition for early hits.

References

1. Singh, P. et al. (2018) // Clinical gastroenterology and hepatology, 16(6), 823-836. 10.1016/j.cgh.2017.06.037

2. Ailioaie, L. M. et al. (2022) // International Journal of Molecular Sciences, 23(14), 7719. 10.3390/ijms23147719

3. Siegel, M. et al. (2007) // Pharmacology & therapeutics, 115(2), 232-245.  10.1016/j.pharmthera.2007.05.003

4. Büchold, C. et al. (2022) // Cells, 11(10), 1667. 10.3390/cells11101667

5. Makurvet, F. D. (2021) // Medicine in Drug Discovery, 9, 100075. 10.1016/j.medidd.2020.100075