Investigation of Potential Mechanisms of Yerba Santa Compounds Against Alzheimer’s Disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which chronic neuroinflammation plays a central role in disease initiation and progression. Yerba Santa (Eriodictyon spp.) is a medicinal plant with reported anti-inflammatory and neuroprotective properties, although its molecular mechanisms remain poorly understood. This study investigated whether chemically characterized Yerba Santa compounds show predicted docking interactions with neuroinflammation-related protein targets implicated in AD. Thirty-six ligand structures, representing 30 mass spectrometry peak assignments, were docked against 30 neuroinflammation-related proteins using the MolSoft ICM molecular docking platform. To improve reproducibility, each ligand–target pair was evaluated by replicated docking simulations followed by statistical analysis, with apo and holo targets evaluated against separate statistical references and expanded docking where applicable. Under the apo −25 kcal/mol screening reference, 11 ligand–target pairs were retained after BH-FDR correction and expanded docking for the apo C1r-C1s (PDB:6F39). Separately, 23 holo ligand–target pairs were retained after comparison with their corresponding redocked native-ligand references: Complement C1q (PDB:2JG8), GABA-A receptor α1β2γ2 (PDB:6D6U), and NLRP3 (PDB:7PZC). The pairs retained under these separate criteria involved multiple Yerba Santa compounds, predominantly flavonoids, while Rosmarinic acid (L21) was retained for both Complement C1q (PDB:2JG8) and NLRP3 (PDB:7PZC). These findings support a selective predicted multi-target interaction profile for Yerba Santa compounds and identify complement signaling, GABA-A receptor-associated neurotransmission, and NLRP3 inflammasome signaling as testable pathways for future experimental studies of neuroinflammation in AD.