Targeting Olokizumab-Interleukin 6 interaction interface to discover novel IL-6 inhibitors.
J Biomol Struct Dyn
; 41(23): 14003-14015, 2023.
Article
em En
| MEDLINE
| ID: mdl-36995131
ABSTRACT
The IL-6/IL-6R or IL-6/GP130 protein-protein interactions play a significant role in controlling the development of chronic inflammatory diseases, such as rheumatoid arthritis, Castleman disease, psoriasis, and, most recently, COVID-19. Modulating or antagonizing protein-protein interactions of IL6 binding to its receptors by oral drugs promises similar efficacy to biological therapy in patients, namely monoclonal antibodies. In this study, we used a crystal structure of the Fab part of olokizumab in a complex with IL-6 (PDB ID 4CNI) to uncover starting points for small molecule IL-6 antagonist discovery. Firstly, a structurebased pharmacophore model of the protein active site cavity was generated to identify possible candidates, followed by virtual screening with a significant database Drugbank. After the docking protocol validation, a virtual screening by molecular docking was carried out and a total of 11 top hits were reported. Detailed analysis of the best scoring molecules was performed with ADME/T analysis and molecular dynamics simulation. Furthermore, the Molecular Mechanics-Generalized Born Surface Area (MM/GBSA) technique has been utilized to evaluate the free binding energy. Based on the finding, one newly obtained compound in this study, namely DB15187, may serve as a lead compound for the discovery of IL-6 inhibitors.Communicated by Ramaswamy H. Sarma.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Interleucina-6
/
Inibidores de Interleucina-6
Tipo de estudo:
Guideline
/
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article