Identification of a novel CDK9 inhibitor targeting the intramolecular hidden cavity of CDK9 induced by Tat binding.
PLoS One
; 17(11): e0277024, 2022.
Article
em En
| MEDLINE
| ID: mdl-36378653
ABSTRACT
HIV-1 transcription is specifically augmented by a transcriptional activator complex composed of Tat, an HIV-1-encoded activator, and the host transcription elongation factor P-TEFb, which is composed of cyclin-dependent kinase 9 (CDK9) and cyclin T1. Several observations suggest that P-TEFb is an attractive anti-HIV-1 drug target. However, the long-term cytotoxicity of CDK9 inhibitors hinders their widespread use in HIV-1 therapy. Thus, novel and safe inhibitors are sorely needed. By performing molecular dynamics simulations of the 3D structure of Tat/P-TEFb, we previously identified a unique cavity structure of CDK9, the CDK9 hidden cavity, that is specifically induced by Tat binding. Here, we attempted to identify compounds that fit this cavity and inhibit CDK9 activity by in silico screening. We identified compounds that could inhibit CDK9 activity. One of such compound, 127, showed the strongest inhibitory activity against CDK9. Interestingly, it also inhibited CDK6 to a similar extent. We inspected the amino acid sequence and structural properties of the CDK9 hidden cavity to determine whether it is conserved in other CDKs, such as CDK6. The Ile61, comprising the center of the CDK9 hidden cavity, appears to be crucial for its kinase activity, thus indicating that the identification of the CDK9 hidden cavity may provide vital information for the development of novel CDK9 inhibitors.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
HIV-1
/
Quinase 9 Dependente de Ciclina
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Idioma:
En
Revista:
PLoS One
Assunto da revista:
CIENCIA
/
MEDICINA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Japão