Molecular Simulation of Oncostatin M and Receptor (OSM-OSMR) Interaction as a Potential Therapeutic Target for Inflammatory Bowel Disease.

Qingqing Du,Weiwei Xue,Yan Qian

doi:10.3389/fmolb.2020.00029

Abstract

Therapeutics targeting cytokines such as the oncostatin M (OSM)-mediated inflammation represent a potential strategy for the treatment of inflammatory bowel disease (IBD). Despite the investigation of the specific role of the interactions between OSM and the receptor (OSMR) in IBD pathogenesis, the 3D structure of the OSM–OSMR complex remains elusive. In this work, the interaction mode between OSM and OSMR at atomic level was predicted by computational simulation approach. The interaction domain of the OSMR was built with the homology modeling method. The near-native structure of the OSM–OSMR complex was obtained by docking, and long-time scale molecular dynamics (MD) simulation in an explicit solvent was further performed to sample the conformations when OSM binds to the OSMR. After getting the equilibrated states of the simulation system, per-residue energy contribution was calculated to characterize the important residues for the OSM–OSMR complex formation. Based on these important residues, eight residues (OSM: Arg100, Leu103, Phe160, and Gln161; OSMR: Tyr214, Ser223, Asp262, and Trp267) were identified as the “hot spots” through computational alanine mutagenesis analysis and verified by additional MD simulation of R100A (one of the identified “hotspots”) mutant. Moreover, six cavities were detected at the OSM–OSMR interface through the FTMap analysis, and they were suggested as important binding sites. The predicted 3D structure of the OSM–OSMR complex and the identified “hot spots” constituting the core of the binding interface provide helpful information in understanding the OSM–OSMR interactions, and the detected sites serve as promising targets in designing small molecules to block the interactions.

Highlights

Inflammatory bowel diseases (IBDs) are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed signal pathways of cytokines such as tumor necrosis factor (TNF)-α and IL-6 (Neurath, 2014)
Compared with the equilibrated state conformation of the wild-type oncostatin M (OSM)– OSM to the receptor (OSMR), significant conformational change near the mutation site occurred in the R100A complex
The interaction between OSM and OSMR was investigated by employing computational simulation techniques including homology modeling, protein–protein docking, and long-time scale molecular dynamics (MD) simulation

Summary

Introduction

Inflammatory bowel diseases (IBDs) are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed signal pathways of cytokines such as tumor necrosis factor (TNF)-α and IL-6 (Neurath, 2014). There are Molecular Simulation of OSM-OSMR Interface still more than 40% of patients who are non-responsive to antiTNF agents, making the discovery of alternative therapeutic targets a priority (Kim et al, 2017). One of those potential targets, oncostatin M (OSM)-mediated inflammation, has gained a lot of interest (Verstockt et al, 2019). It is found that high pretreatment expression of OSM is strongly associated with failure of antiTNF therapy of patients with IBD, which revealed the role of the receptor (OSMR) as part of a unique pathway that contributes to the chronicity of intestinal inflammation (West et al, 2017). Neutralizing OSM antibodies are being developed and should be considered as a novel proof-of-concept trial in IBD patients (West et al, 2017), these developed biological medicines are large, complex, and relatively fragile molecules, which make them difficult and expensive to produce and administer on a large scale (Monaco et al, 2015)

Methods

Results

Conclusion