A Structure-Activity Investigation of the Fungal Metabolite (-)-TAN-2483B: Inhibition of Bruton's Tyrosine Kinase.
Chemistry
; 30(35): e202401051, 2024 Jun 20.
Article
em En
| MEDLINE
| ID: mdl-38629656
ABSTRACT
The natural product (-)-TAN-2483B is a fungal secondary metabolite which displays promising anti-cancer and immunomodulatory activity. Our previous syntheses of (-)-TAN-2483B and sidechain analogues uncovered inhibitory activity against Bruton's tyrosine kinase (Btk), an established drug target for various leukaemia and immunological diseases. A structure-based computational study using ensemble docking and molecular dynamics was performed to determine plausible binding modes for (-)-TAN-2483B and analogues in the Btk binding site. These hypotheses guided the design of new analogues which were synthesised and their inhibitory activities determined, providing insights into the structural determinants of the furopyranone scaffold that confer both activity and selectivity for Btk. These findings offer new perspectives for generating optimised (-)-TAN-2483B-based kinase inhibitors for the treatment of leukaemia and immunological diseases.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Inibidores de Proteínas Quinases
/
Simulação de Dinâmica Molecular
/
Simulação de Acoplamento Molecular
/
Tirosina Quinase da Agamaglobulinemia
Limite:
Humans
Idioma:
En
Revista:
Chemistry
Assunto da revista:
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Nova Zelândia