Enzyme Dynamics Determine the Potency and Selectivity of Inhibitors Targeting Disease-Transmitting Mosquitoes

Area of Science:

• Biochemistry and Molecular Biology
• Insecticide Development
• Computational Chemistry

Background:

• Insecticides are vital for controlling mosquito-borne diseases like malaria and dengue.
• Existing insecticides face challenges of resistance and off-target toxicity.
• There is an urgent need for novel insecticide active ingredients.

Purpose of the Study:

• To identify structural properties for potent and selective noncovalent inhibitors of mosquito acetylcholinesterase 1 (AChE1).
• To understand the differences between Anopheles gambiae AChE1 (AgAChE1) and Mus musculus AChE (mAChE) dynamics.
• To guide the development of new insecticides targeting disease-transmitting mosquitoes.

Main Methods:

• Utilized molecular dynamics simulations to analyze AgAChE1 and mAChE.
• Investigated structural properties influencing inhibitor potency and selectivity.
• Examined the impact of inhibitor binding on enzyme dynamics.

Main Results:

• Distinct collective motions were observed between apo AgAChE1 and mAChE, with AgAChE1 showing reduced dynamics.
• Inhibitor binding decreased overall AChE dynamics, particularly the Ω loop flexibility for potent inhibitors.
• Selectivity for AgAChE1 over mAChE was linked to the α-helix positioning within the binding gorge.

Conclusions:

• Enzyme dynamics are critical considerations for developing effective AChE1 inhibitors.
• Specific structural features, including gorge dynamics and helix positioning, are key for potency and selectivity.
• Findings provide a basis for designing novel, targeted insecticides against disease vectors.