Harnessing Phytoactive Compounds for Targeting Neuroinflammation and Inflammatory Receptors: A Polypharmacology Approach Integrating Molecular Dynamics Simulations and In Silico Formulation Design

Chronic inflammatory and neuroinflammatory disorders—such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS), chronic fatigue syndrome (CFS), and fibromyalgia— pose significant therapeutic challenges due to persistent immune activation leading to neuronal damage and systemic inflammation. The limited efficacy of current treatments has prompted interest in natural agents that can modulate multiple pathological pathways simultaneously. Cucurbita maxima (pumpkin) is increasingly recognized for its diverse phytochemical composition, including phenolic acids, tocopherols, saponins, terpenoids, carotenoids, and polysaccharides—bioactives associated with anti-inflammatory, antioxidant, and neuroprotective effects. The present computational investigation assessed the therapeutic potential of C. maxima compounds in mitigating systemic and neurological inflammation. In silico approaches such as network pharmacology, molecular docking, molecular dynamics (MD) simulations, and ADME (Absorption, Distribution, Metabolism, and Excretion) profiling were employed. Docking results indicated that several pumpkin-derived molecules exhibited strong binding affinities toward key inflammatory and neurodegenerative targets. MD simulations further confirmed the stability of these ligand–protein complexes under physiologically relevant conditions. Despite these promising findings, natural bioactives often face limitations such as poor solubility and low bioavailability, restricting their therapeutic potential. Therefore, computational predictions of formulation strategies, including lipid-based and nanoparticle delivery systems, were explored to enhance drug absorption and bioavailability. This integrative in silico approach highlights C. maxima as a potential multi-target therapeutic candidate against chronic inflammatory and neurodegenerative disorders. While the computational data provide a strong mechanistic basis, experimental and preclinical validation remain essential to confirm efficacy and optimize formulation design. Overall, this study supports the rational development of plant-derived therapeutics aimed at managing complex inflammatory and neurodegenerative conditions.