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.