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Open AccessArticle

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

1
Department of Drug Sciences, Medicinal Chemistry and Pharmaceutical Technology Section, University of Pavia, V.le Taramelli 12, 27100 Pavia, Italy
2
Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstraße 48, 48149 Münster, Germany
3
Department of Chemical and Pharmaceutical Sciences, University of Trieste, 30126 Trieste, Italy
4
Department of Molecular Medicine, Human Physiology Unit, University of Pavia, via Forlanini 6, 27100 Pavia, Italy
5
SCITEC-CNR, via Mario Bianco 9, 20131 Milano, Italy
6
Dipartimento di Chimica, Università di Pavia, V.le Taramelli 12, 27100 Pavia, Italy
7
Department of Medical Biotechnology and Translational Medicine, University of Milan, Via Saldini 50, 20133 Milan, Italy
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(20), 7708; https://doi.org/10.3390/ijms21207708
Received: 17 September 2020 / Revised: 6 October 2020 / Accepted: 14 October 2020 / Published: 18 October 2020
Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective 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 affinity 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 affinity. 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-([1,1’-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 affinity 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 effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent. View Full-Text
Keywords: Sigma-1 receptor; docking; molecular modelling; neuroprotection; neurodegeneration; acetylcholinesterase; aquaporins; oxidative stress Sigma-1 receptor; docking; molecular modelling; neuroprotection; neurodegeneration; acetylcholinesterase; aquaporins; oxidative stress
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Rossino, G.; Rui, M.; Pozzetti, L.; Schepmann, D.; Wünsch, B.; Zampieri, D.; Pellavio, G.; Laforenza, U.; Rinaldi, S.; Colombo, G.; Morelli, L.; Linciano, P.; Rossi, D.; Collina, S. Setup and Validation of a Reliable Docking Protocol for the Development of Neuroprotective Agents by Targeting the Sigma-1 Receptor (S1R). Int. J. Mol. Sci. 2020, 21, 7708.

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