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

FELSZTYNA, IVÁN; MIGUEL, VIRGINIA; GARCÍA, DANIEL ASMED

Córdoba

Congreso; LI Reunión Anual de la Sociedad Argentina de Biofísica; 2023

Sociedad Argentina de Biofísica

The RDL homopentamer is the gamma-aminobutyric acid (GABA) receptor of insects. Thision channel is one of the most important targets for insecticide molecules, some of whichpresent selectivity for this protein over the mammalian GABAA receptors. Given that noexperimental structure is known for the RDL receptor, in a previous work we have shown astrategy based on a retrospective virtual screening (VS) that was used for the obtention ofa reliable RDL homology model. The aim of this work is to use this RDL structure toperform a prospective VS of new non-competitive antagonists that could act asinsecticides. Firstly, in order to refine the VS workflow, different ways of calculating aconsensus scoring were tested by using the docking scores coming from three differentsoftwares (AutoDock Vina, 2Vinardo and Ledock) in the retrospective stage. Thecalculation of the minimum value after the normalization of the docking scores resulted inthe best retrospective VS metrics, so this strategy was selected for the prospectiveworkflow. The compound library used for the prospective VS was built from the ZINC15database. This database was filtered to select chemical compounds with natural origin,available to be experimentally tested and with physico-chemical properties similar tothose of the known active ligands set. With these criteria, 41,373 molecules were used forperforming molecular docking assays. Once the VS ranking was obtained, the compoundsin the top 10 percent were selected to evaluate their potential selectivity for the RDLreceptor over a human GABAA receptor. To achieve this, this set of compounds was dockedon a α1β 2γ2 GABA A receptor heteropentamer (PDB ID: 6X3Z). With these results, aselectivity ranking was built. The compounds located in the first places of this ranking areproposed for their experimental validation as selective RDL insecticides with low affinityfor mammalian GABAA receptors.