Search for possible new GABAergic insecticidal compounds by prospective virtual screening at the fluralaner binding site

GASTALDI MS; FELSZTYNA, I; SANCHEZ-BORZONE M; GARCÍA DA; MIGUEL V

Congreso; LI Reunión Anual Sociedad Argentina de Biofísica; 2023

Isoxazolines are a new family of GABAergic insecticides that act as noncompetitiveantagonists, blocking the insect homopentameric GABAA receptor (RDL). Theseinsecticides have selective toxicity for insects over mammals. Fluralaner, a canonicalrepresentative of this family, binds at the interface of two contiguous subunits, in the areaclose to lipids, at the transmembrane region of the RDL. In the present work, weperformed a prospective ligand-based Virtual Screening consisting in the design of apharmacophore model, based on a common feature pattern shared in a 7 activeisoxazolines-set. Given the ability of the pharmacophore to recover known active ligandsfrom an unknown set of ligands, we used it as a filter to search compounds from the ZINClibrary (containing approx. 20 million compounds available for purchase). Thispharmacophore presents four hydrophobic type interactions and the presence of anaromatic ring, and using this filter allowed us to recover 1 million compounds, whoseactivity on the protein of interest is unknown. These were used to carry out a structurebased Virtual Screening in the fluralaner binding site of the in sílico model of Aedesaegypti RDL, obtained from glutamate-gated chloride channel (GluCl) in an openconformational state as template (PDB ID: 3RHW). As a result, 2886 compounds with thehighest estimated affinity for the receptor were obtained. An exhaustive analysis of thesecompounds in the ZINC15 database, retrieved that the compound ZINC952820 has theGABAA receptor as a potential target protein. This compound belongs to the quinazolinechemical family, which has several members with insecticide activity reported. Weperformed all atom detail Molecular Dynamics Simulations with the virtual screenedcompound and 6 quinazolines whose insecticidal activity has been previously reported inbibliography. For each compound, we characterized the receptor-ligand interactions andspatial stability at the blocking site, and calculated their binding free energy. Theseresults indicate that ZINC952820 and its chemical family share the same binding site asisoxazolines in the RDL. We are carrying out bioassays to verify the insecticidal activity ofZINC952820