Virtual Screening for potential GABAergic insecticides at the fluralaner binding site

GASTALDI, MARÍA SALOMÉ; FELSZTYNA, IVÁN; SÁNCHEZ-BORZONE, MARIELA EUGENIA; GARCÍA, DANIEL ASMED; MIGUEL, VIRGINIA

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

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 shownto act at a site located at the interface between two contiguous subunits, at thetransmembrane region of the receptor. More precisely, outside the pore channel, near tothe lipids area. Fluralaner potently antagonises RDL activity, blocking the chloridechannel. We aim to find new insecticidal compounds that share the same blocking site asfluralaner by pharmacophore- and docking-based virtual screening. We also performedMolecular Dynamics Simulations (MDS) and we pretend to carry out biological assays tovalidate a reduced number of hit compounds. Therefore, we generated a pharmacophoremodel, based on the structural features of 7 active isoxazolines reported in literature. Thispharmacophore was able to retrieve known active compounds from databases. Then, weused the pharmacophore model as a query for the retrieval of potential molecules with thedesired chemical features from the ZINC database (containing approx. 20 millioncompounds). 1 million hit molecules satisfying the pharmacophore model were retrievedand docked at the fluralaner binding site. A 3D model of the Aedes aegyptihomopentamer RDL, developed in our group by homology modelling using the 3RHWtemplate (PDB ID), was used for Molecular Docking assays. As a result, 2886 compoundswith high affinity for the receptor were obtained. We performed ALL ATOM detail MDS witha reduced number of them to characterise the receptor-ligand interactions. The results ofthese interaction analyses will allow us to select only a few compounds to verify theirinsecticidal activity by biological assays.