Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein
that also acts as a chaperone. It is considered as a pluripotent drug target in several
pathologies. The publication of agonist and antagonist bound receptor structures has
paved the way for receptor-based in silico drug design. However, recent studies on
this subject payed no attention to the structural differences of agonist and antagonist
binding. In this work, we have developed a new ensemble docking-based virtual screening
protocol utilizing both agonist and antagonist bound S1R structures. This protocol
was used to screen our in-house compound library. The S1R binding affinities of the
40 highest ranked compounds were measured in competitive radioligand binding assays
and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined.
This way three novel high affinity S1R ligands were identified and one of them exhibited
a notable S1R/S2R selectivity.
