Search for possible new GABAergic insecticidal compounds by prospective Virtual Screening at the fluralaner binding site

GASTALDI, M SALOMÉ; FELSZTYNA, IVAN; SANCHEZ BORZONE, M; GARCIA, DA; MIGUEL, VIRGINIA

Córdoba

Congreso; LI Reunion Anual de la Sociedad Argentina de Biofisica; 2023

Sociedad Argentina de Biofisica

Isoxazolines are a new family of GABAergic insecticides that act as noncompetitive antagonists, blocking the insect homopentameric GABAA receptor (RDL). These insecticides have selective toxicity for insects over mammals. Fluralaner, a canonical representative of this family, binds at the interface of two contiguous subunits, in the area close to lipids, at the transmembrane region of the RDL. In the present work, we performed a prospective ligand-based Virtual Screening consisting in the design of a pharmacophore model, based on a common feature pattern shared in a 7 active isoxazolines-set. Given the ability of the pharmacophore to recover known active ligands from an unknown set of ligands, we used it as a filter to search compounds from the ZINC library (containing approx. 20 million compounds available for purchase). This pharmacophore presents four hydrophobic type interactions and the presence of an aromatic ring, and using this filter allowed us to recover 1 million compounds, whose activity on the protein of interest is unknown. These were used to carry out a structure-based Virtual Screening in the fluralaner binding site of the in sílico model of Aedes aegypti RDL, obtained from glutamate-gated chloride channel (GluCl) in an open conformational state as template (PDB ID: 3RHW). As a result, 2886 compounds with the highest estimated affinity for the receptor were obtained. An exhaustive analysis of these compounds in the ZINC15 database, retrieved that the compound ZINC952820 has the GABAA receptor as a potential target protein. This compound belongs to the quinazoline chemical family, which has several members with insecticide activity reported. We performed all atom detail Molecular Dynamics Simulations with the virtual screened compound and 6 quinazolines whose insecticidal activity has been previously reported in bibliography. For each compound, we characterized the receptor-ligand interactions and spatial stability at the blocking site, and calculated their binding free energy. These results indicate that ZINC952820 and its chemical family share the same binding site as isoxazolines in the RDL. We are carrying out bioassays to verify the insecticidal activity of ZINC952820.