Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R)

Sigma-1 receptor (S1R) is a promising molecular target for the development of novel eective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the anity of small molecules against S1R. The docking method was validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding anity. The druggability profile of the new compounds, with particular reference to the ability to cross the blood–brain barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-d-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,10-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good anity against both S1R and NMDA receptor, good selectivity over S2R and favorable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant eects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.