New insights into the opening of the occluded ligand-binding pocket of Sigma1 receptor: binding of a novel bivalent RC-33 derivative.

Significant progresses have been made to understand the molecular basis of the Sigma1 receptor (S1R) operating in normal and pathological conditions. S1R is a transmembrane protein that participates in a wide variety of processes at the central nervous system; hence, its function has been associated with mental and neurological disorders. Several ligands have been proposed to regulate the function of S1R revealing a high plasticity of the ligand-binding pocket. Previous drug-design studies have been mainly based on pharmacophore models; however, the recently revealed crystal structure of S1R provides an excellent opportunity for verifying previous predictions and for evaluating the binding of novel compounds. Interestingly, the crystal structure shows that the binding pocket of S1R is highly occluded from solvent; therefore, it is not clear how ligands access this site. In the present work, we applied steered molecular dynamics (SMD) simulations to open the occluded ligand-binding pocket in the S1R crysta...