Structure‐Based Screening of Amides with Potential to Overcome <i>Aedes aegypti</i> Insecticide Resistance

Abstract Several natural and synthetic compounds applied as insecticides are amide derivatives. Within the broad spectrum of insecticidal activity of this class of compounds, the activity against Aedes aegypti stands out. The aim of this study was to evaluate the affinity of 27,760 amides for three Ae. aegypti enzymes through structure‐based virtual screening, with the objective of identifying compounds capable of evading the GST defense mechanism. Thirteen low GST‐affinity amides were screened for two other enzymes: Aa AChE1‐involved in the mosquito central nervous system, and Aa FKBP12 ‐ similar to human FKBP12, believed to play a key role in neuroprotective, neurotrophic, and protein folding functions. ADMET analysis showed that amide 6 is unlikely to be toxic to humans. Molecular dynamics analysis demonstrated that amide 6 was less able to interact with the Aa GST active site than the DEET, together with a strong ability to interact with Aa FKBP12. Principal component analysis revealed that complexes with amide 6 present similar conformational trajectories to standard insecticides for Aa AChE1 and Aa FKBP12, together with interestingly different behavior from DEET in Aa GST. Thus, amide 6 seems capable of escaping the Aa GST resistance mechanism and constitutes a promising strategy for the development of specific Ae. aegypti target inhibitors.