Design and Synthesis of inhibitors of tumor necrosis factor-alpha (TNFα) activity of patients with Rheumatoid arthritis (RA)

Abstract

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory cytokine. It acts as a biological regulator of immune function, but its dysregulation is associated with a number of diseases, especially autoimmune diseases. The strategy of inhibiting TNF-α is an excellent treatment option for autoimmune diseases. This study uses computational methods to design potential inhibitors against TNF-α. The Lipinski rule, molecular docking, and ADMET studies identified the results as active agents. They were evaluated to gain insight into the potential binding interaction with the target protein. Based on that, three compounds (MY1, MY2 and MY3) were selected for synthesizing and studying their activity in the laboratory. The molecules were examined for their purity and identity and confirmed by their melting points, FT-IR and H1NMR-spectra. The laboratory evaluation results showed the three compounds classified within the medium toxicity compounds, on the other hand, the values of Kd were (0.129 μM, 10.19 μM, 0.389 μM) and IC50 were (4.34 nM, 4.50 nM and 4.60 nM,) respectively. ΔG has also calculated the values (-9.44 Kcal/ mole), (-6.8 Kcal/ mole) and (8.35 Kcal/ mole). The bonding efficiency scores showed (LE ≤ 0.3), which indicates that all compounds capable of inhibiting TNF-alpha significantly.