Virtual Screening for Ligand Discovery at the σ₁ Receptor

Area of Science:

• Pharmacology
• Computational Chemistry
• Drug Discovery

Background:

• The sigma-1 receptor is a transmembrane protein involved in neurodegenerative diseases, drug addiction, cancer, and pain.
• Current drug discovery efforts for the sigma-1 receptor lack high-throughput functional assays.

Purpose of the Study:

• To develop and validate a high-throughput structure-based computational docking method for discovering novel sigma-1 receptor ligands.
• To identify potent and selective ligands for the sigma-1 receptor.

Main Methods:

• Screened over 6 million compounds using Schrödinger Glide for structure-based computational docking.
• Conducted experimental characterization of top-scoring candidate compounds.
• Assessed ligand affinity (K_D) and selectivity for sigma-1 versus sigma-2 receptors.

Main Results:

• 77% of tested candidates exhibited high-affinity binding to the sigma-1 receptor (K_D < 1 μM).
• Identified compounds with high selectivity for sigma-1 over sigma-2 receptors.
• Discovered compounds showing cross-reactivity between sigma-1 and sigma-2 receptors.

Conclusions:

• Structure-based virtual screening is a highly effective platform for sigma-1 receptor ligand discovery.
• The identified compounds serve as valuable starting points for further studies in sigma-1 receptor biology and therapeutic development.