Molecular modeling and synthesis of inhibitors of herpes simplex virus type 1 uracil-DNA glycosylase.
J Med Chem
; 42(13): 2344-50, 1999 Jul 01.
Article
em En
| MEDLINE
| ID: mdl-10395474
ABSTRACT
We recently reported the properties of the first selective inhibitors of herpes simplex virus type 1 (HSV1) uracil-DNA glycosylase (UDG), an enzyme of DNA repair that has been proposed to be required for reactivation of the virus from latency. 6-(4-Octylanilino)uracil (octAU) was the most potent inhibitor among a series of 6-(4-alkylanilino)uracils, acting in the micromolar range and without effect against human UDG. A 28.5-kDa catalytic fragment of HSV1 UDG has been crystallized in the presence of uracil, and the structure was recently solved. We have used the coordinates of this structure in order to study interaction of our inhibitors with the enzyme, and a model of binding between octAU and UDG has been derived. Starting with the optimized model, the activity of several octAU analogues was predicted, and the values compared favorably with experimental results found for the synthetic compounds. Several hydrophilic derivatives were predicted and found to be active as UDG inhibitors. These compounds will be useful to determine if UDG, like the viral thymidine kinase, is required for reactivation of HSV1 from latency in nerve cells.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Uracila
/
Herpesvirus Humano 1
/
DNA Glicosilases
/
Inibidores Enzimáticos
/
Compostos de Anilina
/
N-Glicosil Hidrolases
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
J Med Chem
Assunto da revista:
QUIMICA
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Estados Unidos