Combined Biophysical Chemistry Reveals a New Covalent Inhibitor with a Low-Reactivity Alkyl Halide.
J Phys Chem Lett
; 9(18): 5275-5280, 2018 Sep 20.
Article
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| MEDLINE
| ID: mdl-30148957
ABSTRACT
17ß-Hydroxysteroid dehydrogenase type 1 (17ß-HSD1) plays a pivotal role in the progression of estrogen-related diseases because of its involvement in the biosynthesis of estradiol (E2), constituting a valuable therapeutic target for endocrine treatment. In the present study, we successfully cocrystallized the enzyme with the reversible inhibitor 2-methoxy-16ß-( m-carbamoylbenzyl)-E2 (2-MeO-CC-156) as well as the enzyme with the irreversible inhibitor 3-(2-bromoethyl)-16ß-( m-carbamoylbenzyl)-17ß-hydroxy-1,3,5(10)-estratriene (PBRM). The structures of ternary complexes of 17ß-HSD1-2-MeO-CC-156-NADP+ and 17ß-HSD1-PBRM-NADP+ comparatively show the formation of a covalent bond between His221 and the bromoethyl side chain of the inhibitor in the PBRM structure. A dynamic process including beneficial molecular interactions that favor the specific binding of a low-reactivity inhibitor and subsequent N-alkylation event through the participation of His221 in the enzyme catalytic site clearly demonstrates the covalent bond formation. This finding opens the door to a new design of alkyl halide-based specific covalent inhibitors as potential therapeutic agents for different enzymes, contributing to the development of highly efficient inhibitors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Inhibidores Enzimáticos
/
Estrenos
/
17-Hidroxiesteroide Deshidrogenasas
Idioma:
En
Revista:
J Phys Chem Lett
Año:
2018
Tipo del documento:
Article
País de afiliación:
Canadá