2D and 3D structure-activity modelling of mosquito repellents: a review

Repellents disrupt the behaviour of blood-seeking mosquitoes protecting humans against their bites which can transmit serious diseases. Since the mid-1950s, N,N-diethyl-m-toluamide (DEET) is considered as the standard mosquito repellent worldwide. However, DEET presents numerous shortcomings. Faced with the heightening risk of mosquito expansion caused by global climate changes and increasing international exchanges, there is an urgent need for a better repellent than DEET and the very few other commercialised repelling molecules such as picaridin and IR3535. In silico approaches have been used to find new repellents and to provide better insights into their mechanism of action. In this context, the goal of our study was to retrieve from the literature all the papers dealing with qualitative and quantitative structure-activity relationships on mosquito repellents. A critical analysis of the SAR and QSAR models was made focusing on the quality of the biological data, the significance of the molecular descriptors and the validity of the statistical tools used for deriving the models. The predictive power and domain of application of these models were also discussed. The hypotheses to compute homology and pharmacophore models, their interest to find new repellents and to provide insights into the mechanisms of repellency in mosquitoes were analysed. The interest to consider the mosquito olfactory system as the target to compute new repellents was discussed. The potential environmental impact of these chemicals as well as new ways of research were addressed.