Development of a Novel <i>Aedes aegypti</i> Repellent: An Integrated Approach Combining In Silico and Bioassays

Aedes aegypti is the most important vector of arboviruses, which are responsible for 3.9 billion cases worldwide. This mosquito seeks a host using its olfactory system, where the odorant-binding protein (OBP) in A. aegypti (AaegOBP1) is essential in sensory communication and is the first filter in odorant selection, which makes this target promising for the development of new repellents. In order to help the AaegOBP1 modulator prioritization, a validated in silico methodology was employed, which enabled the selection of a potential repellent. ZINC71773878 showed a dependency relationship between dosage and repellency activity in bioassays. At the highest concentration used (3000 µmol/100 µL), the ZINC71773878 showed a higher repellency rate than the positive control (N,N-diethyl-3-methylbenzamide [DEET]). The constant pH molecular dynamics (CpHMD) approach employed was able to elucidate the energetic contributions and the effects of different pH on AaegOBP1-ZINC71773878 complex dissociation at pH = 4.0. ZINC71773878 must be prioritized for further trials aiming to develop a new product with repellent activity that is safer and more efficient than the available commercial repellents in Brazil.