The sigma enigma. 3D homology modeling, computer-assisted drug design, 3D pharmacophore-guided docking, MM/PBSA scoring, in silico/in vitro alanine scanning mutagenesis, and functional assay to unveil the sigma-1 receptor hidden secrets.

Originally considered an enigmatic receptor, the sigma1 receptor has recently been identified as a unique ligand-regulated protein. Since its discovery, many studies have shown the potential of sigma1 receptor ligands for the treatment of various diseases of the central nervous system (CNS). However, to date almost no information are available not only the interaction of ligands but also the differences in the interactions of agonists and antagonists with the sigma1 receptor protein have not yet been determined. Under these gloomy perspectives, in this work we embarked in the following, very ambitious task: we i) designed and synthesized novel ligands with high affinity and selectivity for the 1 receptor protein based on our unique in-house developed 3D model of the receptor, and a combination of 3D pharmacophore-based docking (Figure1) and MM/PBSA free energy of binding scoring (1); ii) determined the sigma1 affinity of the ligands in receptor binding studies with radioligands; iii) parallel in silico and experimental site directed mutagenesis experiments yielded a preliminary molecular-based rationale for the agonistic and antagonistic effects of the ligands; These results afforded a dramatic improvement in the understanding of the functions and roles of the sigma1 receptor. This, in turn, will foster the development of news drugs aimed at treating frequent and important human illness such as Alzheimer’s disease, depression, anxiety and pain.