In Search of Synergistic Insect Repellents: Modeling of Muscarinic GPCR Interactions with Classical and Bitopic...

Area of Science:

• Computational chemistry and molecular modeling
• Pharmacology and drug discovery
• Entomology and pest control

Background:

• Insect vector-borne diseases necessitate novel control strategies.
• Muscarinic acetylcholine receptors (mAChRs) are emerging targets for pest control agents.
• Understanding ligand interactions with mAChRs is crucial for developing selective compounds.

Purpose of the Study:

• To investigate the molecular mechanisms of known insect repellents (DEET, IR3535) and muscarine on human and insect mAChRs.
• To characterize early conformational changes in mAChR G protein-coupled receptors (GPCRs) upon ligand binding.
• To design and evaluate a novel, insect-selective, photoswitchable mAChR ligand.

Main Methods:

• Molecular docking and molecular dynamics (MD) simulations were employed.
• Analysis focused on activation microswitches within class A GPCRs.
• A novel bitopic, photoswitchable ligand (BQCA-azo-IR353) was designed and simulated.

Main Results:

• MD simulations elucidated conformational changes in human M1 and fruit fly type-A mAChRs induced by DEET, IR3535, and muscarine.
• Key microswitch groups significantly affected by ligand binding were identified.
• The novel bitopic ligand demonstrated potential for selective interaction with insect mAChRs.

Conclusions:

• Ligand binding induces specific conformational changes in mAChRs, offering insights into their activation pathways.
• The identified microswitches are critical for understanding ligand-receptor interactions.
• Bitopic ligands represent a promising strategy for developing selective and effective insect control agents.