Prospective virtual screening of natural compounds with potential non-competitive antagonistic activity on the RDL GABA-receptor

FELSZTYNA, IVAN; MIGUEL, VIRGINIA; GARCIA, DA

Córdoba

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

Sociedad Argentina de Biofisica

The RDL homopentamer is the gamma-aminobutyric acid (GABA) receptor of insects. This ion channel is one of the most important targets for insecticide molecules, some of which present selectivity for this protein over the mammalian GABAA receptors. Given that no experimental structure is known for the RDL receptor, in a previous work we have shown a strategy based on a retrospective virtual screening (VS) that was used for the obtention of a reliable RDL homology model. The aim of this work is to use this RDL structure to perform a prospective VS of new non-competitive antagonists that could act as insecticides. Firstly, in order to refine the VS workflow, different ways of calculating a consensus scoring were tested by using the docking scores coming from three different softwares (AutoDock Vina, 2Vinardo and Ledock) in the retrospective stage. The calculation of the minimum value after the normalization of the docking scores resulted in the best retrospective VS metrics, so this strategy was selected for the prospective workflow. The compound library used for the prospective VS was built from the ZINC15 database. This database was filtered to select chemical compounds with natural origin, available to be experimentally tested and with physico-chemical properties similar to those of the known active ligands set. With these criteria, 41,373 molecules were used for performing molecular docking assays. Once the VS ranking was obtained, the compounds in the top 10 percent were selected to evaluate their potential selectivity for the RDL receptor over a human GABAA receptor. To achieve this, this set of compounds was docked on a α1β2γ2 GABAA receptor heteropentamer (PDB ID: 6X3Z). With these results, a selectivity ranking was built. The compounds located in the first places of this ranking are proposed for their experimental validation as selective RDL insecticides with low affinity for mammalian GABAA receptors.