Unraveling the Structure of Meclizine Dihydrochloride with MicroED
Abstract Meclizine (Antivert, Bonine) is a first‐generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein‐drug interactions remained unknown. Single‐crystal X‐ray diffraction (SC...
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202306435 |
| _version_ | 1797319228302295040 |
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| author | Jieye Lin Johan Unge Tamir Gonen |
| author_facet | Jieye Lin Johan Unge Tamir Gonen |
| author_sort | Jieye Lin |
| collection | DOAJ |
| description | Abstract Meclizine (Antivert, Bonine) is a first‐generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein‐drug interactions remained unknown. Single‐crystal X‐ray diffraction (SC‐XRD) is previously unsuccessful for meclizine. Today, microcrystal electron diffraction (MicroED) enables the analysis of nano‐ or micro‐sized crystals that are merely a billionth the size needed for SC‐XRD directly from seemingly amorphous powder. In this study, MicroED to determine the 3D crystal structure of meclizine dihydrochloride is used. Two racemic enantiomers (R/S) are found in the unit cell, which is packed as repetitive double layers in the crystal lattice. The packing is made of multiple strong N‐H‐Cl− hydrogen bonding interactions and weak interactions like C‐H‐Cl− and pi‐stacking. Molecular docking reveals the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second‐generation antihistamine) shows the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling elusive drug structures and protein‐drug interactions for precision drug design and optimization. |
| first_indexed | 2024-03-08T04:03:47Z |
| format | Article |
| id | doaj.art-8fbba48bbc7a4c1db24d2dd2d1b546e9 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-03-08T04:03:47Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-8fbba48bbc7a4c1db24d2dd2d1b546e92024-02-09T08:26:35ZengWileyAdvanced Science2198-38442024-02-01116n/an/a10.1002/advs.202306435Unraveling the Structure of Meclizine Dihydrochloride with MicroEDJieye Lin0Johan Unge1Tamir Gonen2Department of Biological Chemistry University of California 615 Charles E. Young Drive South Los Angeles CA 90095 USADepartment of Biological Chemistry University of California 615 Charles E. Young Drive South Los Angeles CA 90095 USADepartment of Biological Chemistry University of California 615 Charles E. Young Drive South Los Angeles CA 90095 USAAbstract Meclizine (Antivert, Bonine) is a first‐generation H1 antihistamine used in the treatment of motion sickness and vertigo. Despite its wide medical use for over 70 years, its crystal structure and the details of protein‐drug interactions remained unknown. Single‐crystal X‐ray diffraction (SC‐XRD) is previously unsuccessful for meclizine. Today, microcrystal electron diffraction (MicroED) enables the analysis of nano‐ or micro‐sized crystals that are merely a billionth the size needed for SC‐XRD directly from seemingly amorphous powder. In this study, MicroED to determine the 3D crystal structure of meclizine dihydrochloride is used. Two racemic enantiomers (R/S) are found in the unit cell, which is packed as repetitive double layers in the crystal lattice. The packing is made of multiple strong N‐H‐Cl− hydrogen bonding interactions and weak interactions like C‐H‐Cl− and pi‐stacking. Molecular docking reveals the binding mechanism of meclizine to the histamine H1 receptor. A comparison of the docking complexes between histamine H1 receptor and meclizine or levocetirizine (a second‐generation antihistamine) shows the conserved binding sites. This research illustrates the combined use of MicroED and molecular docking in unraveling elusive drug structures and protein‐drug interactions for precision drug design and optimization.https://doi.org/10.1002/advs.202306435Meclizine (Antivert, Bonine)Microcrystal electron diffraction (MicroED)Molecular dockingProtein‐drug interactionsRacemic crystal |
| spellingShingle | Jieye Lin Johan Unge Tamir Gonen Unraveling the Structure of Meclizine Dihydrochloride with MicroED Advanced Science Meclizine (Antivert, Bonine) Microcrystal electron diffraction (MicroED) Molecular docking Protein‐drug interactions Racemic crystal |
| title | Unraveling the Structure of Meclizine Dihydrochloride with MicroED |
| title_full | Unraveling the Structure of Meclizine Dihydrochloride with MicroED |
| title_fullStr | Unraveling the Structure of Meclizine Dihydrochloride with MicroED |
| title_full_unstemmed | Unraveling the Structure of Meclizine Dihydrochloride with MicroED |
| title_short | Unraveling the Structure of Meclizine Dihydrochloride with MicroED |
| title_sort | unraveling the structure of meclizine dihydrochloride with microed |
| topic | Meclizine (Antivert, Bonine) Microcrystal electron diffraction (MicroED) Molecular docking Protein‐drug interactions Racemic crystal |
| url | https://doi.org/10.1002/advs.202306435 |
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