Molecular Dynamic Simulation To Reveal the Mechanism Underlying MGL-3196 Resistance to Thyroxine Receptor Beta.
ACS Omega
; 9(19): 20957-20965, 2024 May 14.
Article
em En
| MEDLINE
| ID: mdl-38764645
ABSTRACT
Thyroxine receptor beta (TRß) is a ligand-dependent nuclear receptor that participates in regulating multiple biological processes, particularly playing an important role in lipid metabolism regulation. TRß is currently a popular therapeutic target for nonalcoholic steatohepatitis (NASH), while no drugs have been approved to treat this disease. MGL-3196 (Resmetirom) is the first TRß agonist that has succeeded in phase III clinical trials for the treatment of NASH; therefore, studying its molecular mechanism of action is of great significance. In this study, we employed molecular dynamic simulation to investigate the interaction mode between MGL-3196 and TRß at the all-atom level. More importantly, by comparing the binding patterns of MGL-3196 in several prevalent TRß mutants, it was identified that the mutations R243Q and H435R located, respectively, around and within the ligand-binding pocket of TRß cause TRß to be insensitive to MGL-3196. This indicates that patients with NASH carrying these two mutations may exhibit resistance to the medication of MGL-3196, thereby highlighting the potential impact of TRß mutations on TRß-targeted treatment of NASH and beyond.
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1
Coleções:
01-internacional
Base de dados:
MEDLINE
Idioma:
En
Revista:
ACS Omega
Ano de publicação:
2024
Tipo de documento:
Article