Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation.
J Enzyme Inhib Med Chem
; 39(1): 2353711, 2024 Dec.
Article
em En
| MEDLINE
| ID: mdl-38887057
ABSTRACT
The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 µM). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Relação Dose-Resposta a Droga
/
Avaliação Pré-Clínica de Medicamentos
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Bibliotecas de Moléculas Pequenas
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Antígeno B7-H1
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Receptor de Morte Celular Programada 1
Limite:
Humans
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article