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Oxybutynin (Ditropan), a widely distributed muscarinic antagonist for treating the overactive bladder, has been awaiting a definitive crystal structure for ≈50 years due to the sample and technique limitations. Past reports used powder X-ray diffraction (PXRD) to shed light on the possible packing of the molecule however their model showed some inconsistencies when compared with the 2D chemical structure. These are largely attributed to X-ray-induced photoreduction. Here microcrystal electron diffraction (MicroED) is used to successfully unveil the experimental 3D structure of oxybutynin hydrochloride showing marked improvement over the reported PXRD structure. Using the improved model, molecular docking is applied to investigate the binding mechanism between M3 muscarinic receptor (M3R) and (R)-oxybutynin, revealing essential contacts/residues and conformational changes within the protein pocket. A possible universal conformation is proposed for M3R antagonists, which is valuable for future drug development and optimization. This study underscores the immense potential of MicroED as a complementary technique for elucidating unknown pharmaceutical structures, as well as for protein-drug interactions.

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.

The effects of small amounts of enantiomeric impurities on the vibrational modes of polycrystalline L-histidine (His) were examined using high-frequency-accurate terahertz (THz) spectroscopy. Samples of polycrystalline L-His in its monoclinic form (form B) were grown from an ethanol-rich solvent. D-histidine, ranging from 0.05 to 10.0% in content, was added to the L-His/ethanol-rich solution prior to recrystallization. The crystal forms of all recrystallized samples were first confirmed by high-frequency-accurate THz spectra recorded at 70 K and room-temperature powder X-ray diffraction spectra. A detailed analysis of two spectral features (1.54 and 1.80 THz) measured at 10 K showed that the absorption lines had a narrow linewidth, as well as broad spectral components that could be fitted by Gaussian curves corresponding to defects within the crystals. The shifts in peak frequency with varying amounts of D-His additive in the polycrystalline L-His samples were examined in detail. It was observed that the peak frequency shifted to lower frequencies when small amounts of D-histidine were present and then to higher frequencies when relatively large amounts were present. At low concentrations, D-His molecules are thought to act as impurities that disturb the normal mode vibrations of L-His crystals; however, above certain concentrations, D-His contributes to the formation of a DL racemic crystal. Although the effects of small amounts of D-His molecules in L-His crystals were detectable, quantitative determination of trace amounts of impurity was limited by the complex crystallography of L-His, which includes defects and racemic compounds. [ABSTRACT FROM AUTHOR]

Ferrocenoindenes display planar chirality and thus represent valuable ligands for asymmetric catalysis. Here, we report on the synthesis of novel 3-(1,1-dibromomethylene)ferroceno[1,2-a]indene, (Z)-3-(1-bromomethylene)-6-iodoferroceno[1,2-a]indene, and benzo[5,6-f]ferroceno[2,3,a]inden-1-one. Any application-oriented design of chiral catalysts requires fundamental knowledge about the ligands involved, not only in terms of atom-connectivity, but also in terms of their three-dimensional structure and steric demand. Therefore, the crystal structures of 2-ferrocenylbenzoic acid, ferroceno[1,2-a]indene, and (Z)-3-(1-bromomethylene)-6-iodoferroceno[1,2-a]indene have been determined. The bond-lengths that can be retrieved therefrom also allow for an estimation of the reactivity of the aryl-iodo, bromo-methylidene and dibromomethylidene moieties.

Ferrocenoindenes display planar chirality and thus represent valuable ligands for asymmetric catalysis. Here, we report on the synthesis of novel 3-(1,1- dibromomethylene)ferroceno[1,2-a]indene, (Z)-3-(1-bromomethylene)-6-iodoferroceno[1,2- a]indene, and benzo[5,6-f]ferroceno[2,3,a]inden-1-one. Any application-oriented design of chiral catalysts requires fundamental knowledge about the ligands involved, not only in terms of atom-connectivity, but also in terms of their three-dimensional structure and steric demand. Therefore, the crystal structures of 2-ferrocenylbenzoic acid, ferroceno[1,2-a]indene, and (Z)-3-(1-bromomethylene)-6-iodoferroceno[1,2-a]indene have been determined. The bond-lengths that can be retrieved therefrom also allow for an estimation of the reactivity of the aryl-iodo, bromo-methylidene and dibromomethylidene moieties. [ABSTRACT FROM AUTHOR]

Abstract: Since the introduction of ultra-fast laser techniques for the generation and detection of broadband terahertz pulses, terahertz time-domain spectroscopy has become a versatile tool for vibrational spectroscopy of molecular systems in the far-infrared. Due to their highly collective and delocalized character vibrational modes in this part of the spectrum are highly sensitive to molecular structure and arrangement within a molecular crystal. Here we utilize this sensitivity to differentiate between the enantiopure amino acid l-cysteine and its racemic crystalline dl-form. Using terahertz time-domain spectroscopy we are able to observe temperature induced solid-state phase transitions in polycrystalline dl-cysteine, as well as in polycrystalline benzoic acid. The dynamics of the transitions is studied by tracing the temperature dependency of spectral features that are assigned to certain conformational phases. [Copyright &y& Elsevier]

Abstract: N,N-Diisopropylcarbamoylisatin showed polymorphism and was crystallized into two different space groups, chiral P212121 and racemic P21/c from the solvent; the polymorphism could be controlled by crystallization from the melt using the difference of melting points. [Copyright &y& Elsevier]

In cellular environments, metabolites, peptides, proteins, and other biomolecules can self-assemble into planar and fibrilar molecular crystals. We use atomistic molecular dynamics simulations to show that such biomolecular crystals coupled with low-dimensional materials can form stable hybrid superstructures. We discuss enantiopure and racemic TRP and PHE amino acid crystals adsorbed on or intercalated between graphene, phosphorene, and carbon nanotubes. While racemic biomolecular crystals tend to stay straight in solutions and when adsorbed on flat and cylindrical nanosurfaces, enantiopure crystals undergo twisting. Mixed material properties of these hybrid superstructures can be attractive in many applications.