Evaluation of hesperidin as a potential larvicide against Culex pipiens with computational prediction of its mode of action via molecular docking

Abstract

Hesperidin, a natural flavanone glycoside predominantly found in citrus fruits, has gained attention for its wide-ranging biological activities, including potential insecticidal properties. Culex pipiens, commonly known as the northern house mosquito, is a major vector of several human pathogens, such as the West Nile virus and filariasis, making it a key target in the fight against vector-borne diseases. In this study, we evaluated the larvicidal activity of Hesperidin against Culex pipiens larvae, assessing its potential as an alternative to chemical insecticides. Hesperidin demonstrated potent larvicidal effects, with a lethal concentration 50 (LC₅₀) of 570.3 ± 0.04 µg/mL, outperforming the conventional insecticide Chlorpyrifos 588.3 ± 0.28 µg/mL in efficacy. Molecular docking simulations revealed a strong binding affinity between Hesperidin and crucial neuroreceptors in Culex pipiens, particularly acetylcholinesterase (AChE), a key enzyme involved in nerve signal transmission. The interaction between Hesperidin's hydroxyl groups and the AChE enzyme's active site suggests that AChE inhibition is the primary mechanism driving Hesperidin's insecticidal action. These findings position Hesperidin as a promising, environmentally friendly alternative to synthetic insecticides. However, further research is needed to assess its toxicity to non-target organisms and optimize its formulation for broader application in mosquito control.

Keywords: Culex pipiens; Acetylcholinesterase inhibition; Flavanone glycoside; Hesperidin; Larvicidal activity; Molecular docking; Natural insecticide; Vector control.

Fig. 1

Structure of Hesperidin.

Fig. 2

LDP line graph of Hesperidin compared to a conventional organophosphate insecticide “Chlorpyrifos” against the third larval instar of Culex pipiens.

Fig. 3

2D and 3D molecular interactions of (A) Hesperidin with acetylcholinesterase (AChE) of Culex pipiens compared to (B) the interaction of the conventional AChE inhibitor insecticide Chlorpyrifos with the same receptor. The diagrams on the left illustrate the types of interactions and the key amino acids involved, while the 3D models on the right provide a spatial perspective of these interactions within the AChE binding site. The figure was generated using Molecular Operating Environment (MOE), version 2024.06 (Chemical Computing Group ULC, Montreal, QC, Canada; URL: https://www.chemcomp.com).

Fig. 4

2D and 3D molecular interactions of (A) Hesperidin with nicotinic acetylcholine receptor (nAChR) of Culex pipiens compared to (B) the interaction of the conventional nAChR blocking insecticide Nitenpyram with the same receptor. The diagrams on the left illustrate the types of interactions and the key amino acids involved, while the 3D models on the right provide a spatial perspective of these interactions within the nAChR binding site. The figure was generated using Molecular Operating Environment (MOE), version 2024.06 (Chemical Computing Group ULC, Montreal, QC, Canada; URL: https://www.chemcomp.com).

Fig. 5

2D and 3D molecular interactions of (A) Hesperidin with voltage-gated sodium channel (VGSC) of Culex pipiens compared to (B) the interaction of the conventional VGSC blocking insecticide Indoxacarb (DCJW) with the same receptor. The diagrams on the left illustrate the types of interactions and the key amino acids involved, while the 3D models on the right provide a spatial perspective of these interactions within the VGSC binding site. The figure was generated using Molecular Operating Environment (MOE), version 2024.06 (Chemical Computing Group ULC, Montreal, QC, Canada; URL: https://www.chemcomp.com).

Fig. 6

2D and 3D molecular interactions of (A) Hesperidin with gamma-aminobutyric acid receptor (GABAR) of Culex pipiens compared to (B) the interaction of the conventional GABAR blocking insecticide Fipronil with the same receptor. The diagrams on the left illustrate the types of interactions and the key amino acids involved, while the 3D models on the right provide a spatial perspective of these interactions within the GABAR binding site. The figure was generated using Molecular Operating Environment (MOE), version 2024.06 (Chemical Computing Group ULC, Montreal, QC, Canada; URL: https://www.chemcomp.com).

Fig. 7

Molecular docking interactions of Hesperidin with key neuroreceptors in Culex pipiens. The blue structure represents the ligand Hesperidin, while the green surface indicates the binding pockets of the neuroreceptors. (A) Interaction of Hesperidin with Acetylcholinesterase (AChE), highlighting the fit within the enzyme’s active site. (B) Interaction of Hesperidin with Nicotinic Acetylcholine Receptor (nAChR), demonstrating the binding conformation within the receptor site. (C) Interaction of Hesperidin with Voltage-Gated Sodium Channel (VGSC) α subunit, showing the ligand nestled within the channel’s binding pocket. (D) Interaction of Hesperidin with Gamma-Aminobutyric Acid Receptor (GABAR), illustrating the multiple points of contact between the ligand and the receptor. The figure was generated using Molecular Operating Environment (MOE), version 2024.06 (Chemical Computing Group ULC, Montreal, QC, Canada; URL: https://www.chemcomp.com).