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

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 structure‑based 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

Keywords:

• Interleukin 6
• protein-protein interaction inhibitors
• pharmacophore modeling
• molecular docking
• molecular dynamic simulation

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was supported by the VietNam National Foundation for Science and Technology Development (NAFOSTED) under the Grant Number 108.05-2018.15 (to Quoc-Thai Nguyen).