Computational Analysis of Untapped Natural Compounds of Dodonaea viscosa as a Potential Drug Target against Rheumatoid Arthritis

Abstract

Rheumatoid arthritis is an inflammatory condition that damages joints and cartilage over time. It results in swelling of the synovial lining, which makes movement difficult. Although the exact cause of RA is still unknown, it is well established that genetic and environmental variables have a role in its development. The condition is shown to affect females three times more frequently than males. The WHO estimates that it affects 0.3–1 percent of the world's population. In contrast, the incidence in Pakistan varies from 0.5 to 1.9 percent. There are numerous therapeutic options available for it, including NSAIDs, DMARDs, and biologics. These therapies aid in reducing disease-related symptoms, but their adverse effects have restricted their use. Thus, scientists are looking into herbal plants as a modern remedy for RA that has a high potential for treatment while minimizing side effects and is non-toxic, affordable, and cost-effective. The therapeutic qualities of medicinal plants are derived from bioactive metabolites that help them fight pathogenic diseases. Similarly, Dodonaea viscosa (L.) Jacq., an ethnobotanical plant, was used in this study to assess the effectiveness of its components in the treatment of rheumatoid arthritis. D. viscosa is widely distributed close to Margalla Hills in Pakistan. It is an evergreen, blooming hardy shrub with a variety of plant parts that are said to have anti-inflammatory, antibacterial, wound healing, and antioxidant effects. Phenols, flavonoids, steroids, sterols, saponins, coumarins, tannins, and terpenoids were all detected in D. viscosa ethanol extract. The DPPH and FRAP experiments demonstrated good antioxidant activity. Similarly, D. viscosa extract exhibited significant anti-inflammatory potential in tests like the protein denaturation assay and the HRBC membrane stabilization experiment. In silico studies revealed that nine of the 480 compounds found in D. viscosa ethanol extract had drug-like properties. TNF-α, STAT3, and IL-6 were found to be among the top three RA-related genes in a HUB gene analysis of the top 200 RA genes. The signaling pathways of these genes result in the activation of JAK/STAT, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinases (MAPKs) pathways, respectively. XVIII Significant findings were obtained from the molecular docking analysis of three protein targets with nine ligands. The compound 06, 4-(1-Hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid, had the lowest binding score for TNF-α. Comparatively, compound 7 (3- (2,3-Dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2H-isoindol-1-one) displayed the lowest binding energies for STAT3 and IL-6. The docked complex's highest stability is indicated by its lowest binding energy. The MD simulation findings for these three complexes showed that only compound 6-TNF complex remained stable, proving that compound 06, 4-(1-Hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid, is a good small molecule inhibitor of TNF-α and may one day be employed as a potent drug. The current study concludes that D.viscosa have excellent inhibitory potential against TNF-α, which plays a significant role in the disease. However, additional in-vitro and in vivo testing is strongly advised to assess the efficacy of nine compounds in alleviating the effects of Rheumatoid arthritis progression