Unraveling the Structure of Meclizine Dihydrochloride with MicroED

Abstract

AbstractMeclizine (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.