A Safer Alternative Bio-Repellent: Targeting Mosquito Odorant-Binding Proteins with Catnip-Derived Nepetalactones from <i>Nepeta cataria</i> Leaves

The reliance on synthetic repellents such as N,N-diethyl-meta-toluamide (DEET) has raised health and environmental concerns, prompting the search for safer, plant-derived alternatives. Catnip (Nepeta cataria L.) is a rich source of iridoid monoterpenes, particularly nepetalactones, which are well known for their strong insect-repellent properties. However, the efficient extraction of nepetalactones remains challenging, and their precise mechanisms of action in insect inhibition are not yet fully understood. Thus, this study investigated the chemical composition from various methods, protein–ligand interactions, and pharmacokinetic safety profiles of catnip-derived compounds compared to DEET, with a focus on their interactions with odorant-binding proteins (OBPs) from Anopheles gambiae (AgamOBP), Culex quinquefasciatus (CquiOBP), and Aedes aegypti (AaegOBP). Gas chromatography–tandem mass spectrometry (GC–MS/MS) confirmed the presence of nepetalactone isomers as the major constituents in catnip extracts obtained through stream distillation and dried leaves extracted in olive oil fractions. Molecular docking revealed that cis,cis- and cis,trans-nepetalactones and nepetalactone exhibited high binding affinities, surpassing those of DEET. Molecular dynamics simulations demonstrated that all OBP–ligand complexes achieved stable conformations. Notably, cis,trans-nepetalactone formed a more stable complex with AgamOBP than DEET. These findings suggest that nepetalactones stabilize OBP–ligand interactions while inducing subtle conformational flexibility, potentially disrupting mosquito odorant recognition in a manner distinct from DEET. ADMET predictions indicated that nepetalactones exhibit favorable absorption, distribution, and safety profiles with reduced predicted toxicity compared to DEET. Collectively, these results establish nepetalactones as promising candidates for the development of effective, safe, and sustainable plant-based repellents.