In silico evaluation of neem phytochemicals as modulators of pro-inflammatory cytokines: potential host directed adjuncts for lymphatic filariasis

Lymphatic filariasis (LF) is a neglected tropical disease that causes chronic morbidity through lymphatic dysfunction,

fibrosis, and immune dysregulation. Pro-inflammatory cytokines and chemokines, including TNF-α, IL-6, IL-1β, MIP-1α,

and MIP-1β, are central to LF pathology by amplifying inflammation and promoting tissue remodeling. While mass

drug administration (MDA) effectively targets parasites, it does not reverse established pathology, showing the need

for host‑directed therapies. Neem (Azadirachta indica) contains phytochemicals with immunomodulatory potential. In this study, molecular docking was performed to evaluate the interactions of nimbolide, azadirachtin, and nimbin with

key inflammatory mediators. Nimbolide consistently exhibited the strongest binding affinities to IL 6R (−7.8 kcal/mol),

IL 16 (−7.5 kcal/mol), and TNF a (−7.5 kcal/mol). Azadirachtin showed selective high affinity for TNF-α (−7.1 kcal/

mol), while nimbin demonstrated moderate, broad-spectrum interactions (−5.7 to −6.8 kcal/mol). LigPlot+ analysis con-

firmed stable hydrogen bonding and hydrophobic contacts, especially for nimbolide. Pharmacokinetic predictions using the BOILED-Egg model indicated favorable gastrointestinal absorption for nimbolide and nimbin, with poor blood-brain bar- rier penetration, suggesting systemic efficacy with minimal CNS exposure. Azadirachtin, however, showed poor compliance with drug-likeness and absorption criteria. Neem phytochemicals, especially nimbolide and azadirachtin, may reduce cytokine‑driven inflammation, lymphatic dysfunction, and fibrosis. Although preliminary and computational, the results provide a rational basis for further validation, as well as pharmacokinetic and safety studies. Neem-derived compounds could act as adjuncts to MDA and improve LF morbidity management in endemic regions.