Novel High Affinity Sigma-1 Receptor Ligands from Minimal Ensemble Docking-Based Virtual Screening

Area of Science:

• Pharmacology
• Computational Chemistry
• Neuroscience

Background:

• The sigma-1 receptor (S1R) is a versatile drug target implicated in various diseases.
• Recent advancements include S1R crystal structures bound to agonists and antagonists, enabling structure-based drug design.
• Existing computational studies often overlook the distinct structural binding modes of agonists versus antagonists.

Purpose of the Study:

• To develop and apply an ensemble docking-based virtual screening protocol that incorporates both agonist and antagonist bound S1R structures.
• To identify novel high-affinity S1R ligands from an in-house compound library.
• To evaluate the selectivity of identified S1R ligands against the sigma-2 receptor (S2R).

Main Methods:

• Development of a virtual screening protocol using ensemble docking with both agonist and antagonist bound S1R crystal structures.
• Screening of an in-house compound library against the S1R.
• Experimental validation of top-ranked compounds using radioligand binding assays for S1R affinity and S2R selectivity determination.

Main Results:

• Identification of three novel compounds with high affinity for the sigma-1 receptor.
• One identified compound demonstrated significant selectivity for S1R over S2R.
• The developed virtual screening protocol effectively identified potent S1R ligands.

Conclusions:

• The study successfully identified novel, high-affinity S1R ligands with potential therapeutic applications.
• The developed ensemble docking protocol, considering both agonist and antagonist binding modes, is a valuable tool for S1R drug discovery.
• The selective S1R ligand identified warrants further investigation for its therapeutic potential.