Unraveling the Structure of Meclizine Dihydrochloride with MicroED,Advanced Science

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Unraveling the Structure of Meclizine Dihydrochloride with MicroED
Advanced Science ( IF 14.3 ) Pub Date : 2023-12-03 , DOI: 10.1002/advs.202306435
Jieye Lin ₁ , Johan Unge ₁ , Tamir Gonen _{1,

2,

3}

Affiliation

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.

中文翻译：

用 MicroED 揭示二盐酸美其嗪的结构

Meclizine（Antivert，Bonine）是第一代 H1 抗组胺药，用于治疗晕动病和眩晕。尽管其在医学上的应用已有 70 多年，但其晶体结构和蛋白质与药物相互作用的细节仍然未知。此前，单晶 X 射线衍射 (SC-XRD) 未能成功检测氯苯甲嗪。如今，微晶电子衍射 (MicroED) 能够直接从看似无定形的粉末中分析纳米或微米尺寸的晶体，这些晶体的尺寸仅为 SC-XRD 所需尺寸的十亿分之一。在本研究中，使用 MicroED 来确定二盐酸氯苯甲嗪的 3D 晶体结构。在晶胞中发现了两种外消旋对映体 (R/S)，晶胞在晶格中堆积为重复双层。该堆积由多个强 NH-Cl ^-氢键相互作用和弱相互作用（如 CH-Cl ^-和 pi 堆积）组成。分子对接揭示了氯苯甲嗪与组胺 H1 受体的结合机制。组胺 H1 受体与美其嗪或左西替利嗪（第二代抗组胺药）之间的对接复合物的比较显示了保守的结合位点。这项研究展示了结合使用 MicroED 和分子对接来揭示难以捉摸的药物结构和蛋白质-药物相互作用，以实现精确的药物设计和优化。

更新日期：2023-12-03

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