ABSTRACT
The rational discovery and development of novel insect repellents has challenged researchers for more than six decades. While a number of ligand-based computational methods have been utilized so far, a structure-based approach was until recently unfeasible due to lack of a three-dimensional (3D) structure of an olfactory macromolecule in complex with a repellent. To this end, the report of Anopheles gambiae odorant binding protein 1 (OBP1) crystal structure in complex with the most widely used repellent DEET opened the way for OBP structure-aided repellent discovery. Herein, we provide an overview of the ligand-based quantitative structure–activity relationship (QSAR) studies on repellent amides conducted so far, and we further focus on the impact of AgamOBP1-DEET crystal structure on the design of novel mosquito repellents. Based on this structure, pharmacophore models were constructed to incorporate the essential features of DEET interaction with the protein. The 66pharmacophores were then used for the screening of a divergent set of compounds of known bioactivity followed by molecular docking on the crystal structure of AgamOBP1. Our analysis suggests that a link can be established between the binding mode of a repellent and the observed repellency.
