Molecular Dynamics Characterization of the NCA-II Binding Site in Insect GABAA Receptors and Its Application to Ligand Screening

Objectives: The rapid evolution of insecticide resistance emphasizes the necessity for developing innovative approaches to discover novel insecticides that are highly selective and effective. The second generation of GABAergic Noncompetitive Antagonists (NCA-II), such as isoxazolines, constitutes a recent alternative in the design of new insecticides since they present high potency and selectivity. We aimed to contribute to the development of computational protocols that accelerate the search for new GABAergic insecticides, thereby reducing the costs and time required for their development. Materials and Methods: We performed Molecular Dynamics Simulations of canonical isoxazolines bound to Aedes aegypti GABAAR, to characterize these insecticides interactions at the NCA-II binding site. Following this characterization, we used a protocol for an in silico screening of new compounds that act upon the NCA-II site, combining MDS with ligand and structure-based Virtual Screening. Results: MDS allowed us to identify the main energetic contributions to the interaction between isoxazolines and the receptor, including Van der Waals and hydrogen bonds with residues GLN219, THR257, and ASN264, among others. Additionally, we found that solvation at the binding site reduces this specific interaction. The screening protocol applied enabled us to identify a family of quinazolines with reported insecticidal activity that shares the key interactions previously described. These quinazolines have no reported protein target, and we hypothesize that the insect NCA-II binding site could be a potential target for this family. Conclusion: We believe that this approach offers a valuable strategy for accelerating the search and development of new potential GABAergic insecticides.