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

FELSZTYNA, IVÁN; VILLARREAL, MARCOS A.; GARCÍA DANIEL A.; MIGUEL, VIRGINIA

ACS Omega

American Chemical Society

Año: 2022 vol. 7 p. 1988 - 2001

2470-1343

The RDL receptor is one of the most relevant protein targets for insecticide molecules. It belongs tothe pentameric ligand-gated ion channels (pLGICs) family. Given that experimental structures ofpLGICs 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 homologymodels for virtual screening (VS) have been carried out for pLGICs. The aim of this study was toevaluate which are the determinant factors for a good VS performance using RDL homologymodels, specially analyzing the impact of the template conformational state. Fifteen RDL homologymodels were obtained based on different pLGICs templates representing the closed, open anddesensitized states. A retrospective VS was performed on each model and their performance in theprioritization of active ligands was assessed. In addition, the three best-performing models amongeach of the conformations were subjected to molecular dynamics simulations (MDS) in complexwith a representative active ligand. The models showed variations in their VS performanceparameters that were related to the structural properties of the binding site. VS performance tendedto improve in more constricted binding cavities. The best performance was obtained with a modelbased on a template in the closed conformation. MDS confirmed that the closed model was the onethat best represented the interactions with an active ligand. These results imply that differenttemplates should be evaluated and the structural variations between their channel conformationalstates should be specially examined, providing guidelines for the application of homology modelingfor VS in other proteins of the pLGICs family.