Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters
Albizia julibrissin Durazz is one of the most common herbs used for depression and anxiety treatment, but its mechanism of action as an antidepressant or anxiolytic drug have not been fully understood. We previously isolated and identified one lignan glycoside compound from Albizia Julibrissin Duraz...
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1018473/full |
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| author | Hanhe Liu Yingyao Wu Chan Li Qingfa Tang Qingfa Tang Yuan-Wei Zhang |
| author_facet | Hanhe Liu Yingyao Wu Chan Li Qingfa Tang Qingfa Tang Yuan-Wei Zhang |
| author_sort | Hanhe Liu |
| collection | DOAJ |
| description | Albizia julibrissin Durazz is one of the most common herbs used for depression and anxiety treatment, but its mechanism of action as an antidepressant or anxiolytic drug have not been fully understood. We previously isolated and identified one lignan glycoside compound from Albizia Julibrissin Durazz, (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside (SAG), that inhibited all three monoamine transporters with a mechanism of action different from that of the conventional antidepressants. In this study, we generated homology models for human dopamine transporter and human norepinephrine transporter, based on the X-ray structure of Drosophila dopamine transporter, and conducted the molecular docking of SAG to all three human monoamine transporters. Our computational results indicated that SAG binds to an allosteric site (S2) that has been demonstrated to be formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule connected to the central site (S1) in these monoamine transporters. In addition, we demonstrated that SAG stabilizes a conformation of serotonin transporter with both the extracellular and cytoplasmic pathways closed. Furthermore, we performed mutagenesis of the residues in both the allosteric and orthosteric sites to biochemically validate SAG binding in all three monoamine transporters. Our results are consistent with the molecular docking calculation and support the association of SAG with the allosteric site. We expect that this herbal molecule could become a lead compound for the development of new therapeutic agents with a novel mechanism of action. |
| first_indexed | 2024-04-13T17:33:44Z |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T17:33:44Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-e15cfe93989c41fc9ffc1a00c7fcbb4c2022-12-22T02:37:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.10184731018473Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transportersHanhe Liu0Yingyao Wu1Chan Li2Qingfa Tang3Qingfa Tang4Yuan-Wei Zhang5School of Life Sciences, Guangzhou University, Guangzhou, ChinaSchool of Life Sciences, Guangzhou University, Guangzhou, ChinaSchool of Life Sciences, Guangzhou University, Guangzhou, ChinaSchool of Traditional Chinese Medicine, Southern Medical University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Chinese Medicine Pharmaceutics, Guangzhou, ChinaSchool of Life Sciences, Guangzhou University, Guangzhou, ChinaAlbizia julibrissin Durazz is one of the most common herbs used for depression and anxiety treatment, but its mechanism of action as an antidepressant or anxiolytic drug have not been fully understood. We previously isolated and identified one lignan glycoside compound from Albizia Julibrissin Durazz, (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside (SAG), that inhibited all three monoamine transporters with a mechanism of action different from that of the conventional antidepressants. In this study, we generated homology models for human dopamine transporter and human norepinephrine transporter, based on the X-ray structure of Drosophila dopamine transporter, and conducted the molecular docking of SAG to all three human monoamine transporters. Our computational results indicated that SAG binds to an allosteric site (S2) that has been demonstrated to be formed by an aromatic pocket positioned in the scaffold domain in the extracellular vestibule connected to the central site (S1) in these monoamine transporters. In addition, we demonstrated that SAG stabilizes a conformation of serotonin transporter with both the extracellular and cytoplasmic pathways closed. Furthermore, we performed mutagenesis of the residues in both the allosteric and orthosteric sites to biochemically validate SAG binding in all three monoamine transporters. Our results are consistent with the molecular docking calculation and support the association of SAG with the allosteric site. We expect that this herbal molecule could become a lead compound for the development of new therapeutic agents with a novel mechanism of action.https://www.frontiersin.org/articles/10.3389/fphar.2022.1018473/fullAlbizia julibrissinantidepressantsmechanism of actionserotonin transportermonoamine transportersmolecular docking |
| spellingShingle | Hanhe Liu Yingyao Wu Chan Li Qingfa Tang Qingfa Tang Yuan-Wei Zhang Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters Frontiers in Pharmacology Albizia julibrissin antidepressants mechanism of action serotonin transporter monoamine transporters molecular docking |
| title | Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters |
| title_full | Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters |
| title_fullStr | Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters |
| title_full_unstemmed | Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters |
| title_short | Molecular docking and biochemical validation of (-)-syringaresinol-4-O-β-D-apiofuranosyl-(1→2)-β-D-glucopyranoside binding to an allosteric site in monoamine transporters |
| title_sort | molecular docking and biochemical validation of syringaresinol 4 o β d apiofuranosyl 1 2 β d glucopyranoside binding to an allosteric site in monoamine transporters |
| topic | Albizia julibrissin antidepressants mechanism of action serotonin transporter monoamine transporters molecular docking |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1018473/full |
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