Virtual Screening for potential GABAergic insecticides at the fluralaner binding site

GASTALDI, M SALOMÉ; FELSZTYNA, IVAN; SANCHEZ MA; GARCIA DA; MIGUEL V

Rosario

Congreso; L Reunion Anual de la Sociedad Argentina de Biofisica; 2022

SAB

Fluralaner is a relatively new insecticide and acaricide belonging to the isoxazoline class. Its target is the insect homopentameric GABAA receptor (RDL). Fluralaner has been shown to act at a site located at the interface between two contiguous subunits, at the transmembrane region of the receptor. More precisely, outside the pore channel, near to the lipids area. Fluralaner potently antagonises RDL activity, blocking the chloride channel. We aim to find new insecticidal compounds that share the same blocking site as fluralaner by pharmacophore- and docking-based virtual screening. We also performed Molecular Dynamics Simulations (MDS) and we pretend to carry out biological assays to validate a reduced number of hit compounds. Therefore, we generated a pharmacophore model, based on the structural features of 7 active isoxazolines reported in literature. This pharmacophore was able to retrieve known active compounds from databases. Then, we used the pharmacophore model as a query for the retrieval of potential molecules with the desired chemical features from the ZINC database (containing approx. 20 million compounds). 1 million hit molecules satisfying the pharmacophore model were retrieved and docked at the fluralaner binding site. A 3D model of the Aedes aegypti homopentamer RDL, developed in our group by homology modelling using the 3RHW template (PDB ID), was used for Molecular Docking assays. As a result, 2886 compounds with high affinity for the receptor were obtained. We performed ALL ATOM detail MDS with a reduced number of them to characterise the receptor-ligand interactions. The results of these interaction analyses will allow us to select only a few compounds to verify their insecticidal activity by biological assays.