Assessment of insect RDL receptor homology models for virtual screening: impact of the template conformational state in pLGICs

FELSZTYNA, I; VILLARREAL MA; GARCÍA DA; MIGUEL V

Congreso; XLIX Reunión Anual Sociedad Argentina de Biofísica; 2021

Sociedad Argentina de Biofisica

Pentameric ligand-gated ion channels (pLGICs) constitute a large family oftransmembrane receptors. This family includes the γ-aminobutyric acid (GABA) receptors.The RDL homopentamer is the main GABA receptor in the insect nervous system. Itpresents structural differences with vertebrate GABAA receptors that result in a particularpharmacological profile. Therefore, the RDL receptor (RDL-R) is one of the most relevanttargets for insecticides. Due to the difficulties related to pLGICs crystallization, manystudies have used homology modeling to obtain the structure of these proteins and toperform computational studies about their ligands binding. However, the impact that thetemplate conformational state could have on the model virtual screening(VS) performance has not been studied in detail. The aim of this work is to obtain RDL-Rhomology models in different conformational states and to evaluate their performance in aretrospective VS of channel-blocker insecticides. Fifteen RDL-R models were obtained,based on different pLGICs templates, whose structures represent three conformationalstates: closed, open and desensitized. With these models, molecular docking assays wereperformed with a set of active ligands and decoys. To evaluate the VS performance, thearea under the ROC curve and the BEDROC score were calculated for each of the models.In addition, molecular dynamics simulations (MDS) were performed for the best modelsamong each of the conformational states. The initial structures were obtained from thedocking poses of the insecticide fipronil. VS performance parameters showed variationsaccording to the conformational state of the templates. The correlations of theseparameters with different variables were evaluated to analyze which were the determinantfactors for a correct identification of active ligands. Structural properties of the channelpore, such as the solvent-accessible area and volume and the pore diameter at somespecific residues could explain the differences in VS performance. The best results wereobtained for a model based on a closed template. MDS confirmed that theexpected interactions between the binding site residues and fipronil were present only inthe closed model. These results show that different templates should be explored to obtainaccurate RDL homology models, particularly focusing on the template conformationalstate. The model that presented the best performance parameters could be used in aprospective VS.