Integrated Computational and Experimental Evaluation of Ellagic Acid as a Natural Phosphodiesterase-4 Inhibitor for the Management of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD); Ellagic acid; Phosphodiesterase-4 (PDE4); Molecular docking; Molecular dynamics simulation; MM-GBSA; Antiinflammatory activity; cAMP
AuthorsAbstractBackground: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease of the respiratory tract; it causes considerable morbidity and mortality worldwide. Phosphodiesterase-4 (PDE4) is a validated target for drug development, and PDE4 inhibitors increase intracellular cAMP and inhibit inflammatory signals. However, the adverse effects of the PDE4 inhibitors currently available (including roflumilast) have restricted their clinical use, which makes natural PDE4 inhibitors with fewer adverse effects more desirable. Methods: An integrated computational and experimental approach was used to discover natural PDE4 inhibitors from an Ayurvedic phytoconstituent library, which consisted of 250 phytoconstituents. The prioritized compounds after physicochemical filtering and pharmacophore-based virtual screening were then docked into the catalytic domain of PDE4 (PDB ID: 4WCU) and subsequently the binding free energies of these selected chemicals were computed using MM-GBSA approach. The prioritized compounds were also evaluated for their ADMET, toxicity and 200_ns MD simulation. Ellagic acid was chosen as the lead compound and further tested in the in vitro antioxidant (DPPH) and BEAS-2B cell viability (SRB), pro-inflammatory cytokine (TNF-α, IL-6, and IL-1β) and nitric oxide inhibition and intracellular cAMP assays. Results: Molecular docking revealed that Ellagic acid had a Glide XP score of −9.262 kcal/mol and MM-GBSA binding free energy of −72.56 kcal/mol with the catalytic pocket of PDE4 and showed stable hydrogen bonding with some key catalytic residues such as TYR159, ASP318, GLN369 and PHE372 for favourable binding. Molecular dynamics simulations showed that the PDE4–Ellagic acid complex exhibited minimal conformational changes of the protein and ligand during the 200 ns simulation and that the protein–ligand interactions were maintained. In silico ADMET and toxicity prediction indicated acceptable pharmacokinetic properties, and a favourable predicted safety profile. In vitro, Ellagic acid had strong antioxidant activity (DPPH IC₅₀ ≈ 38 µg/mL), low cytotoxicity to BEAS-2B cells (IC₅₀ = 735.4 µg/mL) and significantly reduced the production of TNF-α, IL-6, IL-1β and nitric oxide in LPS stimulated RAW264.7 macrophages, and restored intracellular cAMP levels in inflamed BEAS-2B cells, supporting modulation of the PDE4/cAMP signaling pathway. Conclusions: The combination of computational and experimental results shows that Ellagic acid is a promising natural lead compound for PDE4 targeting therapy for COPD. All these properties indicate that it is highly favourable for binding, stable molecular interactions, an acceptable predicted pharmacokinetic profile, potent antioxidant activity, anti-inflammatory properties and the ability to restore intracellular cAMP, which indicate further investigation and preclinical development. However, biochemical PDE4 enzyme inhibition assays and in vivo efficacy assays need to be undertaken to verify its therapeutic potential and mechanism of action.
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