The molecular mechanism of the effects of the anti-neuropathic ligands on the modulation of the Sigma-2 receptor: An in-silico study.

Neuropathic pain (NP) is a prevalent medical condition that lacks an effective treatment. Recently, the Sigma-2 receptor (S2R) has been proposed as a potential therapeutic target for NP. Some highly-selective S2R ligands (UKH1114, CM398, and YTD) have shown promising results in vivo, but the molecular interaction between the S2R and these ligands has been scarcely investigated. This work explores changes in the S2R upon interaction with the three mentioned ligands using in silico approaches. The results indicated that the ICL1, H1, ICL2, and ECL are the most dynamic regions of S2R in all systems. Binding interaction analysis identified amino acids with significant contribution to the binding free energy. Notably, the UKH1114-S2R simulation trajectory revealed that small alterations in the ICL1, H1, ICL2, and ECL form a new stable opening in the S2R, linking the occluded S2R binding pocket to the endoplasmic reticulum lumen, providing more evidence for the assumptions about the EBP and S2R mechanism of function. Further, the agreement between the membrane parameters in our study and experimental values confirms the validity of the MD simulations. Overall, this study provides new insights into the interaction between anti-NP ligands and the S2R. • Among ligand-S2R complexes, YTD showed the highest binding affinity. • UKH1114 induced significant conformational changes and caused tunnel formation in the S2R. • Water and ions could enter the formed tunnel in the UKH1114-S2R tunnel. [ABSTRACT FROM AUTHOR]