Computational Screening of IL-1 and IL-6 Inhibitors for Rheumatoid Arthritis: Insights from Molecular Docking and Dynamics Analysis

Background: Rheumatoid arthritis (RA) remains a significant therapeutic challenge due to its chronic inflammatory nature. Consequently, many patients turn to alternative therapies, such as herbal compounds and supplements, when conventional treatments prove relatively ineffective or cause adverse side effects. Some compounds are being investigated for their potential to alleviate RA symptoms or manage disease. This study aimed to evaluate the anti-inflammatory effects of selected herbal compounds targeting the Interleukin-1 (IL-1) and Interleukin-6 (IL-6) pathways, key inflammatory regulators in RA. Specifically, the study assessed the binding affinity, stability, and dynamics of IL-1 and IL-6 inhibitory compounds as potential therapeutic agents for RA. Methods: In silico experiments were conducted with herbal compounds to modulate IL-1 and IL-6 signaling. Computational techniques, including molecular docking, molecular dynamics (MD) simulations, Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations, Absorption, Distribution, Metabolism, and Excretion (ADME) analysis, toxicity predictions, and Density Functional Theory (DFT) analysis, were employed to investigate these interactions comprehensively. Results: Neoglucobrassicin demonstrated the strongest binding affinity for IL-6 (Total score: -349.00 kJ/mol), followed by Galbelgin (-338.00 kJ/mol). For IL-1β, CID21722980 exhibited the highest binding affinity (-273.14 kJ/mol), with Eupaformosanin ranking second (-264.29 kJ/mol). Neoglucobrassicin formed interactions with multiple IL-6 residues, indicating a stable binding complex, while CID21722980 similarly interacted with key IL-1β residues, forming stable complexes. Both the Neoglucobrassicin-IL6 and CID21722980- IL1β complexes demonstrated structural stability, as evidenced by Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF) stabilizing towards the end of the 100 ns molecular dynamics (MD) simulation. MM-GBSA analysis revealed the highest binding energy for the IL-6-Neoglucobrassicin complex (-43.70 kcal/mol), while CID21722980 showed strong affinity for IL-1β (-43.29 kcal/mol), suggesting enhanced binding potential. Additionally, Density Functional Theory (DFT) analysis of the Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies revealed electron distribution patterns in Neoglucobrassicin and CID21722980 that support their potential therapeutic applications. Discussion: The strong binding affinities, stable molecular dynamics (MD) simulations, and favorable ADMET and DFT properties of Neoglucobrassicin and CID21722980 underscore their potential as antiinflammatory agents targeting IL-6 and IL-1β. The mechanistic insights into their inhibitory effects on these targets suggest multifaceted anti-inflammatory properties, warranting further in vivo and clinical investigations. Conclusion: Neoglucobrassicin and CID21722980 demonstrated promising binding affinities, favorable pharmacokinetic profiles, and advantageous electronic properties, positioning them as strong candidates for further exploration in anti-inflammatory therapies. These findings highlight the potential of these herbal compounds as modulators of IL-6 and IL-1β, paving the way for future drug development.