Exploring Neem Phytochemicals as Potential Inhibitors of Anopheles gambiae Trehalose-6-Phosphate Synthase

Increasing resistance to insecticides and their accompanying off-target effects call for the development of biodegradable insecticides with selective metabolism-based targets. Anopheles gambiae trehalose-6-phosphate synthase ( Ag TPS), the first enzyme in the trehalose metabolic pathway, is essential for key developmental processes in the organism but absent in vertebrates, making it an attractive insecticidal target. This study aims to evaluate the inhibitory potential of neem-derived compounds against Ag TPS using in silico methods. The 3D structure was predicted, and its active-site residues were identified based on conserved TPS homologues. A library of 275 neem phytochemicals was compiled from IMPPAT and Dr Duke’s databases, alongside known substrates and inhibitors. Molecular docking was performed using AutoDock Vina at the glucose-6-phosphate (G6P), UDP-glucose (UDPG), and combined binding sites. Protein–ligand interactions were analysed using LigPlot+, while insecticide-likeness and ADMET properties were evaluated using QEPest and pkCSM. Several neem-derived compounds exhibited stronger binding affinities to Ag TPS than the natural substrates across all binding sites. Tannic acid showed a high binding affinity across all binding sites, with a range of -11.3 to -12.1 kcal/mol, showing interactions with conserved catalytic residues. Other compounds, including 1-cinnamoylmelianolone, nimbilin, 6-acetylnimbandiol, and 7-deacetyl-7-oxogedunin, also demonstrated strong and consistent binding, frequently outperforming known TPS inhibitors. ADMET analysis revealed that tannic acid possessed unfavourable pharmacokinetic and toxicity profiles. In contrast, limonoids such as 1-cinnamoylmelianolone and nimbilin displayed a more favourable balance between potency, insecticide-likeness, and predicted safety. Neem-derived phytochemicals show significant potential as inhibitors of Ag TPS, supporting Ag TPS as a promising target for selective mosquito control. While tannic acid demonstrates strong binding affinity, its poor drug-likeness limits practical application. The limonoids, such as 1-cinnamoylmelianolone and nimbilin, thus emerge as more viable lead candidates. These findings provide molecular insights into neem’s insecticidal activity and support further experimental validation for vector control applications.