Investigation of the Effects and Mechanism of Selected Phytoconstituents Against Rheumatoid Arthritis: Network Pharmacology, Molecular Docking, ADMET and Drug Likeness Property Analysis

ABSTRACT The progressive and destructive nature of rheumatoid arthritis, with marked symptoms of joint inflammation, synovial hyperplasia, bone and cartilage destruction, pain, stiffness, and functional impairment, poses a significant threat to the public health. In this study, we performed a computational screening of 40 phytochemical constituents against glyceraldehyde 3-phosphate dehydrogenase (GAPDH) using network pharmacology, molecular docking, ADMET prediction, and molecular dynamics simulation to generate hypotheses regarding possible phytoconstituent–target interactions relevant to RA-associated inflammatory pathways. Among the 40 phytoconstituents, the top three with the strongest binding affinities were astragaloside, ellagic acid, and wilforlide A. The strong interactions of astragaloside with the target protein, as revealed by the docking process, involved conventional hydrogen bonding and van der Waals interactions with key interacting amino acid residues, such as ALA C:238 and LEU B:203. In contrast, ellagic acid exhibited fewer conventional hydrogen bonds but greater π interactions (π-alkyl and π-sigma) with the key interacting amino acid residues ALA E:238 and GLN D:204, respectively. Similarly, wilforlide A demonstrated conventional hydrogen bonding without π interactions with GLY D:12 as the key amino acid residue. It also exhibited unfavorable donor-donor interactions with the amino acid residue CYS D:152. Pharmacokinetic analysis of the top-ranked phytoconstituents, astragaloside, ellagic acid, and wilforlide A, revealed favorable ADME profiles. Similarly, toxicity predictions revealed that the LD 50 values of the top three most favorable chemical constituents, astragaloside, ellagic acid, and wilforlide A, were 5000 mg/kg, 2991 mg/kg, and 2589 mg/kg, respectively. Astragaloside exhibited active nephrotoxicity and immunotoxicity, ellagic acid exhibited active nephrotoxicity and carcinogenicity, and wilforlide A exhibited only active immunotoxicity. Molecular dynamics simulations suggested that the astragaloside–GAPDH complex maintained relative conformational stability under simulated conditions. Overall, the docking, ADMET, toxicity, and molecular dynamics results prioritized astragaloside and ellagic acid for further experimental evaluation. These findings should be interpreted as computational hypotheses only and do not establish the therapeutic efficacy, target selectivity, or clinical relevance in RA.