Insect RDL Receptor Models for Virtual Screening: Impact of the Template Conformational State in Pentameric...

Area of Science:

• Structural Biology
• Computational Chemistry
• Pharmacology

Background:

• The RDL receptor, a pentameric ligand-gated ion channel (pLGIC), is a crucial target for insecticides.
• Experimental structures of pLGICs are challenging to obtain, necessitating the use of homology modeling.
• The utility of homology models for virtual screening (VS) in pLGICs remains largely unevaluated.

Purpose of the Study:

• To assess the factors influencing virtual screening (VS) performance using RDL receptor homology models.
• To specifically investigate the impact of template conformational states (closed, open, desensitized) on VS efficacy.
• To provide guidelines for employing homology modeling in VS for pLGICs.

Main Methods:

• Generated fifteen RDL homology models using diverse pLGIC templates representing different conformational states.
• Conducted retrospective virtual screening (VS) on each model to evaluate ligand prioritization.
• Performed molecular dynamics simulations (MDS) on top-performing models complexed with an active ligand.

Main Results:

• Homology model VS performance varied, correlating with binding site structural properties, favoring more constricted cavities.
• The best VS performance was achieved using a homology model derived from a closed-state pLGIC template.
• MDS corroborated that the closed-state model best represented interactions with an active ligand.

Conclusions:

• Template selection and examination of conformational state variations are critical for successful VS using homology models.
• Closed-state homology models appear most suitable for virtual screening of RDL receptor ligands.
• Findings offer a framework for applying homology modeling to VS for other pLGIC family members.