Targeting Olokizumab-Interleukin 6 interaction interface to discover novel IL-6 inhibitors

Area of Science:

• Biochemistry
• Pharmacology
• Drug Discovery

Background:

• Interleukin-6 (IL-6) protein-protein interactions are crucial in chronic inflammatory diseases like rheumatoid arthritis and COVID-19.
• Oral small molecule antagonists offer a promising alternative to biologic therapies, such as monoclonal antibodies, for modulating IL-6 activity.

Purpose of the Study:

• To identify potential small molecule inhibitors of IL-6 by leveraging structural information of existing IL-6 antagonists.
• To discover novel lead compounds for the development of orally administered IL-6 antagonists.

Main Methods:

• Generated a structure-based pharmacophore model using the crystal structure of olokizumab complexed with IL-6 (PDB ID: 4CNI).
• Performed virtual screening of the DrugBank database using molecular docking.
• Validated the docking protocol and analyzed top hits with ADME/T predictions and molecular dynamics simulations.
• Evaluated binding free energy using Molecular Mechanics-Generalized Born Surface Area (MM/GBSA).

Main Results:

• Identified 11 top candidate molecules through virtual screening and molecular docking.
• Detailed analysis revealed DB15187 as a promising compound with favorable predicted properties.
• MM/GBSA calculations supported the binding affinity of the identified compounds.

Conclusions:

• DB15187 emerged as a potential lead compound for the development of novel IL-6 inhibitors.
• This study provides a foundation for designing orally bioavailable drugs targeting IL-6 pathways.
• The findings may pave the way for new therapeutic strategies against IL-6-mediated inflammatory conditions.