Molecular Docking Study of Positive Allosteric Modulators of the Sigma-1 Receptor for the COVID treatment of elderly patients

Purpose: Our goal with this project is to determine conformations of ligands that have strong affinities to allosteric sites of the Sigma-1 Receptor (Sig1R). The SARS-CoV-2 strain virus is part of a group of viruses known as RNA Positive Sense Coronaviruses. The virus enters the cell through endocytosis and replicates in a cellular compartment derived for the Endoplasmic Reticulum (ER). Viral replication causes ER stress and forces the cell to adapt. The Sig1R found within the membranes of the nucleus, ER, and mitochondria. The receptor protein can change conformation to help the cell cope with ER stress. Positive Allosteric Modulators (PAMs) bind to the Sig1R and cause conformational changes that can alter its response to natural ligand binding. By targeting the Sig1R we can create therapeutic responses to the SARS-CoV-2 virus by modulating ER stress response signaling pathways for elderly patients. Method: We performed molecular docking for the Nonselective, Selective and Putative ligands of Sig1R.With molecular docking, we were able to determine the binding affinities and conformations of three types of PAMs in relation to the Sig1R. Results: The study showed that nonselective allosteric modulators have the strongest binding affinities for the Sig1R. Through molecular docking and 3D visualization, the data showed that most PAMs bind to the monomeric Sig1R at an orthosteric binding site. The only ligand to bind at a site other than the orthosteric site was SCH23390. The rest of the ligands bound to the receptor at the orthosteric site, which would indicate that they would need to compete with the receptor's natural ligands for binding. To avoid the competition, the PAMs need to bind to the receptor at a site different from their first pose, or most preferred configuration. Conclusion: This project showed us that non-selective PAMs have a higher binding affinity. We were also able to identify a need to explore other binding configurations, besides the first pose, to find allosteric binding of the PAMs to the Sig-1R.