title: Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study.
abstract: Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine's enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Guoxun
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Xue
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Panpan
authors.initials: P
authors.lastname: Wang
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Fengyuan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Li
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou 730000, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Yao
authors.affiliation: Innovative Drug Research and Bioinformatics Group, Innovative Drug Research Centre and School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
mesh_terms: D020816:Amino Acid Motifs; D014150:Antipsychotic Agents / Q000737:chemistry* / Q000378:metabolism; D000069445:Atomoxetine Hydrochloride / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D006801:Humans; D008376:Maprotiline / Q000737:chemistry / Q000378:metabolism; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009025:Morpholines / Q000737:chemistry* / Q000378:metabolism; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry* / Q000378:metabolism; D009638:Norepinephrine / Q000737:chemistry* / Q000378:metabolism; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D000077593:Reboxetine; D013237:Stereoisomerism; D040681:Structural Homology, Protein; D013816:Thermodynamics; D014745:Viloxazine / Q000737:chemistry / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D009025:Morpholines; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; D008376:Maprotiline; D000069445:Atomoxetine Hydrochloride; D014745:Viloxazine; D000077593:Reboxetine; D009638:Norepinephrine