Reducing the Flexibility of Typeâ
II Dehydroquinase for Inhibition: A Fragment-Based Approach and Molecular Dynamics Study.
ChemMedChem
; 12(18): 1512-1524, 2017 09 21.
Article
en En
| MEDLINE
| ID: mdl-28791799
ABSTRACT
A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would decrease the flexibility of the substrate-covering loop (catalytic loop) of the typeâ
II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance. Chemical modification of its non-aromatic moiety through an olefin cross-metathesis and Seebach's self-reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme's catalytic cycle. Molecular dynamics simulations revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active site.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Diseño de Fármacos
/
Inhibidores Enzimáticos
/
Simulación de Dinámica Molecular
/
Hidroliasas
Idioma:
En
Revista:
ChemMedChem
Asunto de la revista:
FARMACOLOGIA
/
QUIMICA
Año:
2017
Tipo del documento:
Article
País de afiliación:
España
Pais de publicación:
ALEMANHA
/
ALEMANIA
/
DE
/
DEUSTCHLAND
/
GERMANY