Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Design of dual inhibitors of human TNF-α and IL-6 with potentials for the treatment of rheumatoid arthritis

Shu-Qiang Wang, Meng Shi, Lei Fang, Sheneg-Ming Xu, Cong Wang, Zhong-Xiang Yu

Department of Orthopedic Surgery, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China;

For correspondence:-

Accepted: 19 October 2019 Published: 30 November 2019

Citation: Wang S, Shi M, Fang L, Xu S, Wang C, Yu Z. Design of dual inhibitors of human TNF-α and IL-6 with potentials for the treatment of rheumatoid arthritis. Trop J Pharm Res 2019; 18(11):2305-2312 doi: 10.4314/tjpr.v18i11.11

© 2019 The authors.
This is an Open Access article that uses a funding model which does not charge readers or their institutions for access and distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0) and the Budapest Open Access Initiative (http://www.budapestopenaccessinitiative.org/read), which permit unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited..

Abstract

Purpose: To design dual inhibitors of tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) with potentials for the treatment of rheumatoid arthritis (RA).

Methods: Tumor necrosis factor α (TNF-α) and IL-6 were investigated as potential drug targets for the treatment of RA. Dual inhibitors targeting both TNF-α and IL-6 were designed simultaneously using molecular docking simulation-based in silico virtual screening technique. National Cancer Institute (NCI) diversity set-II consisting of 1818 diverse ligands were screened against both drug targets in order to identify potential lead molecules on the basis of lowest binding energy.

Results: Out of 1818 diverse ligand molecules present in the NCI diversity set-II, five lead molecules were selected based on best binding interactions with both target receptors. The results of toxicity profiling showed that compounds ZINC19701771 and ZINC06576501 lacked major toxicity-associated functional groups linked to mutagenic, tumorigenic, irritant and reproductive effects. However, ZINC03898665 and ZINC05015095 possessed some mutagenic and reproductive effects. Compound ZINC01757986 also showed a high chance of mutagenicity.

Conclusion: These results indicate that the two lead molecules (ZINC19701771 and ZINC06576501) that showed reliable physicochemical properties can serve as potential candidates for development of anti-arthritis drug for effective inhibition of human TNF-α and IL-6 receptors.

Keywords: Rheumatoid arthritis, Docking, Interleukin-6, Tumor necrosis factor α, Toxicity