https://www.selleckchem.com/products/ethyl-3-aminobenzoate-methanesulfonate.html Inflammation is a natural process that occurs in the organism in response to harmful external agents. Despite being considered beneficial, exaggerated cases can cause severe problems for the body. The main inflammatory manifestations are pain, increased temperature, edema, decreased mobility, and quality of life for affected individuals. Diseases such as arthritis, cancer, allergies, infections, arteriosclerosis, neurodegenerative diseases, and metabolic problems are mainly characterized by an exaggerated inflammatory response. Inflammation is related to two categories of substances pro- and anti-inflammatory mediators. Among the pro-inflammatory mediators is tumor necrosis factor-α (TNF-α). It is associated with immune diseases, cancer, and psychiatric disorders that increase its excretion. Thus, it becomes a target widely used in discovering new anti-inflammatory drugs. In this context, secondary metabolites biosynthesized by plants have been used for thousands of years and continue to be one of the primary sources of new drug scaffolds against inflammatory diseases. To minimize costs related to the drug discovery process, computer-aided drug design (CADD) techniques are broadly explored to increase the chances of success. In this review, the main natural compounds that are derived from alkaloids, flavonoids, terpene, and polyphenols as promising TNF-α inhibitors will be discussed. Finally, we applied a molecular modeling protocol involving all compounds described here, suggesting that their interactions with Tyr59, Tyr119, Tyr151, Leu57, and Gly121 residues are essential for the activity. Such findings may prove useful for research groups worldwide to design new anti-inflammatory TNF-α inhibitors. Berberine (BBR) is an isoquinoline alkaloid extracted from Chinese medicine, exerting various pharmacological effects. BBR is partially metabolized by cytochrome 3A4 (CYP3A4) in vivo. Some