Prediction of Novel Insecticides for Malaria Prevention: Virtual Screening and Molecular Dynamics of AgAChE Inhibitors

Malaria is a prominent vector-borne disease, with a high mortality rate, particularly in children under five years old. Despite the use of various insecticides for its control, the emergence of resistant mosquitoes poses a significant public health threat. Acetylcholinesterase (AChE) is a crucial enzyme in nerve transmission and a primary target for insecticide development due to its role in preventing repeated nerve impulses. Recent studies have identified difluoromethyl ketone (DFK) as a potent inhibitor of both sensitive and resistant Anopheles gambiae acetylcholinesterase (AgAChE). This study aimed to identify novel AgAChE inhibitors that could be explored for malaria prevention. We performed a virtual screening on the PubChem database using a pharmacophore model from difluoromethyl ketone-inhibited AgAChE's crystal structure. The most promising compound was then subjected to molecular docking and dynamics studies with AgAChE to confirm initial findings. ADMET and agrochemical likeness (ag-like) properties were also analyzed to assess its potential as an agrochemical agent. PubChem18463786 was identified as the most suitable compound from the virtual screening. Molecular docking and molecular dynamics studies confirmed its strong in-teraction with AgAChE. The ADMET and ag-like analyses indicated that Pub-Chem18463786 possesses physicochemical properties suggesting a high probability of non-absorption in humans and meets the criteria for agrochemical similarity. Our findings suggest that PubChem18463786 is a potential AgAChE inhibitor candidate. After validation through in vitro and in vivo experiments, it could be ex-ploited for malaria prevention and serve as a lead compound for the synthesis of new, more effective, and selective agrochemical agents.