EXPLORING THE IMMUNOSTIMULANT POTENTIAL OF DRYOPTERIS COCHLEATA PHYTOCOMPOUNDS: AN IN SILICO APPROACH

Abstract

Background: Chronic inflammation is a hallmark of several autoimmune and inflammatory disorders, including psoriasis, rheumatoid arthritis, inflammatory bowel disease, and diabetes mellitus. Pro-inflammatory cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and interferon-gamma (IFN-γ) play crucial roles in the initiation and progression of inflammatory responses, making them attractive therapeutic targets. Natural products continue to represent an important source of bioactive molecules for the development of safer anti-inflammatory agents.

Objective: The present study aimed to investigate the anti-inflammatory potential of selected phytoconstituents from Dryopteris cochleata through molecular docking, pharmacokinetic prediction, and molecular dynamics simulation against IL-1β, IL-6, and IFN-γ.

Methods: The crystal structures of IL-1β (PDB ID: 4DEP), IL-6 (PDB ID: 1ALU), and IFN-γ (PDB ID: 1FG9) were retrieved from the RCSB Protein Data Bank and prepared using the Schrödinger Protein Preparation Wizard. Five phytoconstituents identified from D. cochleata and the reference drug levamisole were subjected to molecular docking using the Glide Standard Precision protocol. Pharmacokinetic properties were evaluated using the SwissADME platform and the BOILED-Egg model. The stability of the most promising protein–ligand complexes was further assessed by 100 ns molecular dynamics simulation using Desmond, followed by RMSD, RMSF, radius of gyration (Rg), solvent-accessible surface area (SASA), principal component analysis (PCA), and free energy landscape (FEL) analyses.

Results: Molecular docking demonstrated that Gibberellin A3, Aspidinol, and Quercetin exhibited favorable binding affinities toward IL-6, while Gibberellin A3 showed the strongest interaction with IL-1β. Ferulic acid displayed the highest binding affinity toward IFN-γ. Quercetin exhibited the highest docking score against IL-6 (−6.522 kcal/mol), whereas Gibberellin A3 showed the strongest binding toward IL-1β (−6.866 kcal/mol), both outperforming the reference drug levamisole. SwissADME analysis indicated that Aspidinol possessed the most favorable pharmacokinetic profile, with high gastrointestinal absorption, appropriate lipophilicity, and acceptable drug-likeness. Gibberellin B also demonstrated high gastrointestinal absorption despite its relatively high topological polar surface area, whereas Quercetin showed comparatively poor intestinal absorption because of its higher polarity. None of the evaluated compounds were predicted to cross the blood-brain barrier. Molecular dynamics simulations confirmed the stability of the selected protein–ligand complexes throughout the 100 ns simulation period, as evidenced by acceptable RMSD, RMSF, Rg, SASA, PCA, and FEL analyses, indicating stable intermolecular interactions under physiological conditions.

Conclusion: The integrated computational analyses suggest that phytoconstituents of Dryopteris cochleata, particularly Aspidinol and Gibberellin A3, possess promising anti-inflammatory potential through favourable binding interactions with key inflammatory cytokines and acceptable pharmacokinetic characteristics. These findings support further in vitro and in vivo investigations to validate their therapeutic potential as novel anti-inflammatory agents. Overall, the computational analyses indicate that the phytoconstituents of Dryopteris cochleata may act as immunomodulators rather than direct immune stimulants, as they target key cytokines responsible for regulating both innate and adaptive immune responses. Their favorable docking scores, stable molecular dynamics behavior, and strong MM/GBSA binding energies suggest the potential to modulate cytokine signaling, thereby enhancing immune responsiveness while maintaining immune homeostasis. These findings provide a mechanistic basis for the traditional use of D. cochleata and support further biological validation through experimental studies.