Scholarlink

<p>Ivermectin is lethal to <i>Anopheles</i> 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 <i>Caenorhabditis elegans,</i> 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 <i>Anopheles dirus</i> and <i>Anopheles minimus</i> 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 <i>Anopheles</i> 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 <i>Anopheles</i> GluCl M2-M3 loop. This hydrogen bond is possible due to a single substitution in the M2-M3 loop from <i>C. elegans</i> ILE273 to <i>Anopheles</i> THR304. The work presented here improves our understanding of <i>Anopheles</i> GluCl-ivermectin interactions as well as how ivermectin resistance could arise in the future.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Lethal effects of ivermectin structures on malaria vectors and in silico analysis of interactions with their glutamate-gated chloride ion channels

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月10日

查看全文
  • Minh N. Nguyen,
  • Andrew K. Jones,
  • David Hotwagner,
  • Pattarapon Khemrattrakool,
  • Thitipong Hongsuwong,
  • Borimas Hanboonkunupakarn,
  • Podjanee Jittamala,
  • Patchara Sriwichai,
  • Joel Tarning,
  • Kevin C. Kobylinski

摘要

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.