Local Scaffold Diversity-Contributed Generator for Discovering Potential NLRP3 Inhibitors.
J Chem Inf Model
; 64(3): 737-748, 2024 02 12.
Article
em En
| MEDLINE
| ID: mdl-38258981
ABSTRACT
Deep generative models have become crucial tools in de novo drug design. In current models for multiobjective optimization in molecular generation, the scaffold diversity is limited when multiple constraints are introduced. To enhance scaffold diversity, we herein propose a local scaffold diversity-contributed generator (LSDC), which can be utilized to generate diverse lead compounds capable of satisfying multiple constraints. Compared to the state-of-the-art methods, molecules generated by LSDC exhibit greater diversity when applied to the generation of inhibitors targeting the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3). We present 12 molecules, some of which feature previously unreported scaffolds, and demonstrate their reasonable docking binding modes. Consequently, the modification of selected scaffolds and subsequent bioactivity evaluation lead to the discovery of two potent NLRP3 inhibitors, A22 and A14, with IC50 values of 38.1 nM and 44.43 nM, respectively. And the oral bioavailability of compound A14 is very high (F is 83.09% in mice). This work contributes to the discovery of novel NLRP3 inhibitors and provides a reference for integrating AI-based generation with wet experiments.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Proteína 3 que Contém Domínio de Pirina da Família NLR
Limite:
Animals
Idioma:
En
Revista:
J Chem Inf Model
Assunto da revista:
INFORMATICA MEDICA
/
QUIMICA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China