In Silico Characterization of Growth Differentiation Factors as Inhibitors of TNF-Alpha and IL-6 in Immune-Mediated Inflammatory Disease Rheumatoid Arthritis.

Ghulam Mustafa,Hafiza Salaha Mahrosh,Rawaba Arif

doi:10.1155/2021/5538535

Ghulam Mustafa, Hafiza Salaha Mahrosh + Show 1 more

Open Access

https://doi.org/10.1155/2021/5538535

Copy DOI

Abstract

Tumor necrosis factor alpha (TNF-α) plays a critical role in the progression of inflammation and affects the cells of the synovial membrane. Another key factor in the progression of rheumatoid inflammation is interleukin-6 (IL-6). Both TNF-α and IL-6 promote the proliferation of synovial membrane cells thus stimulating the production of matrix metalloproteinases and other cytotoxins and leading towards bone erosion and destruction of the cartilage. Growth differentiation factor-11 (GDF11) and growth differentiation factor-8 (GDF8) which is also known as myostatin are members of the transforming growth factor-β family and could be used as antagonists to inflammatory responses which are associated with rheumatoid arthritis. In the current study, to elucidate the evolutionary relationships of GDF11 with its homologs from other closely related organisms, a comprehensive phylogenetic analysis was performed. From the phylogram, it was revealed that the clade of Primates that belong to superorder Euarchontoglires showed close evolutionary relationships with order Cetartiodactyla of the Laurasiatheria superorder. Fifty tetrapeptides were devised from conserved regions of GDF11 which served as ligands in protein-ligand docking against TNF-α and IL-6 followed by drug scanning and ADMET profiling of best selected ligands. The peptides SAGP showed strong interactions with IL-6, and peptides AFDP and AGPC showed strong interactions with TNF-α, and all three peptides fulfilled all the pharmacokinetic parameters which are important for bioavailability. The potential of GDF8 as an antagonist to TNF-α and IL-6 was also explored using a protein-protein docking approach. The binding patterns of GDF8 with TNF-α and IL-6 showed that GDF8 could be used as a potential inhibitor of TNF-α and IL-6 to treat rheumatoid arthritis.

Highlights

The immune system is a collection of chemicals, cells, and pathways that protect the cells from foreign invaders
From the phylogeny of Growth differentiation factor-11 (GDF11), it was inferred that O. cuniculus had the strongest evolutionary relationship with Ochotona princeps while H. sapiens with Gorilla gorilla gorilla
The Primates order that belongs to superorder Euarchontoglires is showing more identity with order Cetartiodactyla of the Laurasiatheria superorder, inferring that there would be some evolutionary closeness between two orders

Summary

Introduction

The immune system is a collection of chemicals, cells, and pathways that protect the cells from foreign invaders. Adaptive immunity is an antigendependent response activated upon the subsequent exposure of host cells to antigens. There is synergy between the events in innate immunity and adaptive immunity, and any defect in either system provokes severe problems and diseases such as autoimmune diseases, inflammations, and immunodeficiency disorders [2]. The immune system undergoes processed pathways to initiate self-tolerance to avoid the destruction of tissues or cells of the host immune system. Mounting evidence has clearly demonstrated the relation of innate immunity responses in initiation, progression, and maintenance of different autoimmune disorders including lupus erythematosus, rheumatoid arthritis, Alzheimer’s disease, Addison’s disease, and type I diabetes mellitus [2]. Autoimmunity involves the BioMed Research International self-destruction of own tissues by the production of abnormal responses due to self-reactive T-cells, cytokines, and autoantibodies. To design potential drugs and targets, these self-reactive species are the main focus to maintain different autoimmune disorders [4]

Methods

Results

Conclusion