Exploring Structural Requirements for Sigma‑1 Receptor Linear Ligands: Experimental and Computational Approaches

Sigma-1
receptor (S1R) is involved in a large array of biological
functions due to its ability to interact with various proteins and
ion channels. Crystal structures of human S1R revealed the trimeric
organization for which each protomer comprises the ligand binding
pocket. This study applied a multistep computational procedure to
develop a pharmacophore model obtained from molecular dynamics simulations
of available cocrystal structures of well-known S1R ligands. Apart
from the well-established positive ionizable and hydrophobic features,
the obtained model included an additional specific hydrophobic feature
and different excluded volumes, thus increasing the selectivity of
the model as well as a more detailed determination of the distance
between two essential features. The obtained pharmacophore model passed
the validation test by receiver operating characteristic (ROC) curve
analysis of active and inactive S1R ligands. Finally, the pharmacophoric
performance was experimentally investigated through the synthesis
and binding assay of new 4-phenylpiperazine-based compounds. The most
active new ligand 2-(3-methyl-1-piperidyl)-1-(4-phenylpiperazin-1-yl)­ethanone
(3) showed an S1R affinity close to the reference compound
haloperidol (Ki values of 4.8 and 2.6
nM, respectively). The proposed pharmacophore model can represent
a useful tool to design and discover new potent S1R ligands.