Insect RDL Receptor Models for Virtual Screening: Impact of the Template Conformational State in Pentameric Ligand-Gated Ion Channels

The RDL receptor is one of the most relevant protein targets for insecticide molecules. It belongs to the pentameric ligand-gated ion channel (pLGIC) family. Given that the experimental structures of pLGICs are difficult to obtain, homology modeling has been extensively used for these proteins, particularly for the RDL receptor. However, no detailed assessments of the usefulness of homology models for virtual screening (VS) have been carried out for pLGICs. The aim of this study was to evaluate which are the determinant factors for a good VS performance using RDL homology models, specially analyzing the impact of the template conformational state. Fifteen RDL homology models were obtained based on different pLGIC templates representing the closed, open, and desensitized states. A retrospective VS process was performed on each model, and their performance in the prioritization of active ligands was assessed. In addition, the three best-performing models among each of the conformations were subjected to molecular dynamics simulations (MDS) in complex with a representative active ligand. The models showed variations in their VS performance parameters that were related to the structural properties of the binding site. VS performance tended to improve in more constricted binding cavities. The best performance was obtained with a model based on a template in the closed conformation. MDS confirmed that the closed model was the one that best represented the interactions with an active ligand. These results imply that different templates should be evaluated and the structural variations between their channel conformational states should be specially examined, providing guidelines for the application of homology modeling for VS in other proteins of the pLGIC family.

Automated summary

This study evaluated the usability of homology models in virtual screening (VS) for the RDL receptor, a relevant protein target for insecticide molecules. The impact of template conformational states on VS performance was analyzed. Homology models based on different pLGIC templates representing closed, open, and desensitized states were obtained. Their performance in prioritizing active ligands was assessed, and the best-performing models were subjected to molecular dynamics simulations. The results showed that the structural properties of the binding site and the template conformational state influenced the VS performance. Models with more constricted binding cavities tended to have better performance, and the closed conformation template produced the best results. These findings provide guidance for the application of homology modeling in virtual screening for other proteins in the pLGIC family.