In silico studies of the open form of human tissue transglutaminase.

Autor: Ivashchenko SD; Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701.; Laboratory of Microbiology, BIOTECH University, Moscow, Russia, 125080., Shulga DA; Department of Chemistry, Moscow State University, Moscow, Russia, 119991., Ivashchenko VD; Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701., Zinovev EV; Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701., Vlasov AV; Moscow Institute of Physics and Technology, Dolgoprudny, Russia, 141701. aleksei.vlasov@phystech.edu.; Laboratory of Microbiology, BIOTECH University, Moscow, Russia, 125080. aleksei.vlasov@phystech.edu.; Joint Institute for Nuclear Research, Dubna, Russia, 141980. aleksei.vlasov@phystech.edu.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 Jul 10; Vol. 14 (1), pp. 15981. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1038/s41598-024-66348-8
Abstrakt: Human tissue transglutaminase (tTG) is an intriguing multifunctional enzyme involved in various diseases, including celiac disease and neurological disorders. Although a number of tTG inhibitors have been developed, the molecular determinants governing ligand binding remain incomplete due to the lack of high-resolution structural data in the vicinity of its active site. In this study, we obtained the complete high-resolution model of tTG by in silico methods based on available PDB structures. We discovered significant differences in the active site architecture between our and known tTG models, revealing an additional loop which affects the ligand binding affinity. We assembled a library of new potential tTG inhibitors based on the obtained complete model of the enzyme. Our library substantially expands the spectrum of possible drug candidates targeting tTG and encompasses twelve molecular scaffolds, eleven of which are novel and exhibit higher binding affinity then already known ones, according to our in silico studies. The results of this study open new directions for structure-based drug design of tTG inhibitors, offering the complete protein model and suggesting a wide range of new compounds for further experimental validation.
(© 2024. The Author(s).)
Databáze: MEDLINE
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