Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory condition that can lead to increased death rates, severe disability, and destructive joint damage. The prevalence of RA is the most frequent of all inflammatory diseases and is reported to affect 0.1-2.0% of the population worldwide. The incidence and disability-adjusted life years rates of RA in India have shown an increasing trend from 1990 to 2021. In the current investigation, a pharmacoinformatics approach was used to explore the potential synthetic derivative compounds of curcumin against unexplored hub genes associated with the therapeutics of RA in the Indian population. Such investigations could not only cut short the in-vitro and in-vivo experimental approaches. Herein, a GWAS of RA was conducted in a genetically distinct Indian population. CD4, STAT4, and CCR6 genes were identified and reconfirmed by a few previously reported GWAS findings, which revealed CCR6 as one of the key targets associated with RA. Lipinski's rule was used to determine the adsorption, distribution, metabolism, and excretion of ligands for drug suitability, and acute toxicity was also predicted. However, further docking analysis was carried out for curcumin and its nine derivatives against CCR6, STAT4, and CD4 human proteins compared with standards, i.e., Methotrexate and Hydroxychloroquine. Based on molecular docking, toxicity, and pharmacokinetics, the MD simulation study was observed for CCR6, STAT4, and CD4 with Methotrexate complex, Hydroxychloroquine complex, and pentagamavuton complex, respectively. This study revealed pentagamavuton as an active therapeutic that majorly inhibits the activity of the pivotal receptor CCR6, STAT4, and CD4 in humans. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00547-7.