Selectivity mechanism of BCL-XL/2 inhibition through in silico investigation.
Phys Chem Chem Phys
; 24(28): 17105-17115, 2022 Jul 21.
Article
em En
| MEDLINE
| ID: mdl-35791860
ABSTRACT
The BCL-XL protein is among the most important members of the anti-apoptotic subfamily of the BCL-2 protein family, and is currently a promising new target for anti-tumor drug research. However, the BCL-XL/2 proteins have similar structures and functions, which could lead to undesirable side effects because of inhibitors that can bind to both BCL-XL and BCL-2. Therefore, it is crucial to expound on the structural basis of the selective mechanism towards BCL-XL/2 inhibition. In the current study, we employed hybrid computational methods including molecular docking and dynamics simulation, MM/GBSA energy calculation, alanine scanning mutagenesis and Hirshfeld surface analysis to comprehensively reveal the selectivity mechanism towards BCL-XL/2 from multiple perspectives, revealing the significant effects of the BCL-XL residues SER106 and LEU108 as well as the BCL-2 residue ASP103 on the inhibitory selectivity. Overall, our findings provide useful references for the rational design of BCL-XL/2 selective inhibitors with better affinity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-bcl-2
/
Antineoplásicos
Idioma:
En
Revista:
Phys Chem Chem Phys
Assunto da revista:
BIOFISICA
/
QUIMICA
Ano de publicação:
2022
Tipo de documento:
Article