Nguyen, M. N., Jones, A. K., Hotwagner, D., Khemrattrakool, P., Hongsuwong, T., Hanboonkunupakarn, B., Jittamala, P., Sriwichai, P., Tarning, J., & Kobylinski, K. C. (2026). Lethal effects of ivermectin structures on malaria vectors and in silico analysis of interactions with their glutamate-gated chloride ion channels. Scientific Reports, 16(1). https://doi.org/10.1038/s41598-026-39698-8
Abstract:
Ivermectin is lethal to Anopheles mosquitoes making it a possible malaria control intervention. The
primary mode of action of ivermectin occurs when it binds to the glutamate-gated chloride channel
(GluCl), allowing for continuous flow of chloride leading to flaccid paralysis and death of the mosquito.
In Caenorhabditis elegans, ivermectin is thought to open the GluCl channel when the M2-M3 loop forms
Van der Waals bonds with the first sugar ring and aglycone structure of ivermectin. Here we investigate
in Anopheles dirus and Anopheles minimus the mosquito-lethal effect of ivermectin (both sugar rings),
monosaccharide (one sugar ring), and aglycone (no sugar rings) demonstrating full, partial, and no
effect, respectively. The Anopheles GluCl protein sequences were determined and used to a create 3-D
structural docking models. The docking models identified new binding interactions with a hydrogen
bond forming between the second sugar ring hydroxyl group (4″-OH) and THR304 of the Anopheles
GluCl M2-M3 loop. This hydrogen bond is possible due to a single substitution in the M2-M3 loop from
C. elegans ILE273 to Anopheles THR304. The work presented here improves our understanding of
Anopheles GluCl-ivermectin interactions as well as how ivermectin resistance could arise in the future.
License type:
Attribution 4.0 International (CC BY 4.0)
Funding Info:
This research / project is supported by the Singapore Food Agency (SFA), National Research Foundation - Singapore Food Story R&D 2.0 Programme
Grant Reference no. : NRF-SFSRND2FF-0001
This research / project is supported by the A*STAR - Career Development Award/Fund
Grant Reference no. : 222D800029
Description:
This is a post-peer-review, pre-copyedit version of an article published in Scientific Reports. The final authenticated version is available online at: http://dx.doi.org/10.1038/s41598-026-39698-8.