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Computational Characterization of the Selective Inhibition of Human Norepinephrine and Serotonin Transporters by Escitalopram Scaffold

Abstract

Human norepinephrine and serotonin transporters (hNET and hSERT) are closely related monoamine transporters (MATs) that regulate neurotransmitters signaling in neurons and are primary targets for a wide range of therapeutic drugs used in treatment of mood disorders. The subtle modifications of escitalopram scaffold exhibit distinct selective inhibition profiles of hNET and hSERT. However, the structural details of escitalopram scaffold binding to hSERT and (or) hNET are poorly understood and still remain a great challenge. In this work, on the basis of more recently solved X-ray crystallographic of hSERT in complex with escitalopram, a total of 3 μs all-atom MD simulation and binding free energies calculation via MM/GB(PB)SA, thermodynamic integration (TI) and MM/3D-RISM methods were performed to reproduce experimental free energies. And both MM/GBSA and TI has the high correlation coefficient (R2 = 0.95 and 0.96, respectively) between the relative binding free energies of calculated and experimental values. Furthermore, MM/GBSA per-residue energy decomposition, molecular interaction fingerprints and thermodynamics-structure relationship analysis were employed to investigate and characterize the selectivity of escitalopram scaffold with three modifications (escitalopram, ligand10 and talopram) for hNET and hSERT. As a result, 4 warm spots (A73, Y151, A477 and I481) in hNET and 4 warm spots (A96, A173, T439 and L443) in hSERT were thus discovered to exert a pronounced effect on the selective inhibition of hNET and hSERT by the studied ligands. These simulation results would provide great insight into the design of inhibitors with the desired selectivity to hNET and hSERT, thus further promoting the research of more efficacious antidepressants.

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Publication details

The article was accepted on 30 Oct 2018 and first published on 31 Oct 2018


Article type: Paper
DOI: 10.1039/C8CP06232C
Citation: Phys. Chem. Chem. Phys., 2018, Accepted Manuscript
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    Computational Characterization of the Selective Inhibition of Human Norepinephrine and Serotonin Transporters by Escitalopram Scaffold

    G. Zheng, F. Yang, T. Fu, G. Tu, Y. Chen, X. Yao, W. Xue and F. ZHU, Phys. Chem. Chem. Phys., 2018, Accepted Manuscript , DOI: 10.1039/C8CP06232C

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