COMPUTATIONAL SCREENING OF POTENTIAL AChE INHIBITORS IN ANOPHELES GAMBIAE: TOWARDS OVERCOMING INSECTICIDE RESISTANCE

Background: Insecticide resistance in Anopheles gambiae poses a major challenge to malaria vector control. The G119S mutation in acetylcholinesterase (AChE) is associated with resistance to organophosphate and carbamate insecticides, while glutathione S-transferases (GSTs) can contribute to metabolic resistance. This study aimed to identify candidate AChE inhibitors using hierarchical virtual screening, with additional computational filtering against glutathione S-transferase delta (GSTD). 
Methods: The AChE structure (PDB ID: 6ARY), containing the G119S variant, and the GSTD structure (PDB ID: 1PN9) were prepared using AutoDockTools 1.5.6. A library of five million commercially available compounds from Mcule was screened against AChE, and compounds with predicted binding scores below −6.5 kcal/mol were selected for subsequent docking against GSTD. Compounds with predicted GSTD binding affinities stronger than that of glutathione (−5.2 kcal/mol) were excluded. The remaining complexes were assessed using Discovery Studio Visualizer 4.5, and four selected candidates were redocked using AutoDock Vina 1.1.2 and compared with chlorpyrifos. 
Results: Initial screening predicted 982 compounds with AChE binding scores below −6.5 kcal/mol. Sequential filtering based on docking and interaction with GSTD yielded four candidate compounds. All four were positioned within the AChE active-site gorge and exhibited several interactions involving Cys447. All four candidates had more favorable predicted docking scores than chlorpyrifos (−6.5 kcal/mol). 
Conclusion: The virtual screening identified four commercially available compounds with favorable predicted binding to AChE and comparatively weak predicted binding to GSTD under the applied docking criteria. These compounds need further investigation through biochemical inhibition assays, metabolic stability studies, and bioassays against insecticide-resistant An. gambiae to establish their inhibitory activity and potential relevance to insecticide resistance control.