Chemical Shift-Dependent Interaction Maps in Molecular Solids

Abstract

Structure determination of molecular solids through NMR crystallography relies on the generation of a comprehensive set of candidate crystal structures and on the comparison of chemical shifts computed for those candidates with experimental values. Exploring the polymorph landscape of molecular solids requires extensive computational power, which leads to a significant bottleneck in the generation of the set of candidate crystals by crystal structure prediction (CSP) protocols. Here, we use a database of crystal structures with associated chemical shifts to construct three-dimensional interaction maps in molecular crystals directly derived from a molecular structure and its associated set of experimentally measured chemical shifts. We show how the maps obtained can be used to identify structural constraints for accelerating CSP protocols and to evaluate the likelihood of candidate crystal structures without requiring DFT-level chemical shift computations.

Multitasking Pharmacophores Support Cabotegravir-Based Long-Acting HIV Pre-Exposure Prophylaxis (PrEP)

“…To better address the mechanism of the low water solubility of cabotegravir, we have aimed to map the structural differences of cabotegravir passing from solids to solution. We have chosen NMR spectroscopy for this purpose as the chemical shift, an NMR parameter that could be obtained feasibly in both solids and solution, is highly suitable for reporting the conformational changes of molecules [ 17 , 18 , 19 , 20 , 21 , 22 , 23 ]. Chemical shifts could be influenced by other factors besides the molecular structural changes, in particular, the polarity change of the molecular environments (e.g., solvent vs. crystal lattice) and the intermolecular packing.…”

Polymorph Identification for Flexible Molecules: Linear Regression Analysis of Experimental and Calculated Solution- and Solid-State NMR Data

“…While a stable solid crystalline form provides one of the best means to achieve these goals, success is frequently hampered by the occurrence of other polymorphs . The intricate energy landscape of both crystallization and crystals means that polymorphs often have closely positioned local energy-minima, and novel polymorphs can consequently continue to emerge throughout the development process. − Distinguishing, understanding, and characterizing these forms allows the emergence of unwanted forms to be somewhat derisked, and so various techniques are typically applied to do so, especially X-ray diffraction (XRD) and solid-state nuclear magnetic resonance (NMR) in conjunction with density functional theory (DFT) calculations. − Differences in crystal packing interaction networks provide a means to distinguish similar crystal structures, notably by probing local environments derived from NMR chemical shifts. − Solid-state NMR provides valuable insight into intermolecular interactions, − which can be incorporated into crystal structure prediction (CSP) , and machine learning (ML) frameworks, − providing, for example, geometry constraints for improved prediction of crystal structures. , …”

“… 7 − 9 Differences in crystal packing interaction networks provide a means to distinguish similar crystal structures, notably by probing local environments derived from NMR chemical shifts. 10 − 13 Solid-state NMR provides valuable insight into intermolecular interactions, 14 − 19 which can be incorporated into crystal structure prediction (CSP) 20 , 21 and machine learning (ML) frameworks, 22 − 25 providing, for example, geometry constraints for improved prediction of crystal structures. 26 , 27 …”

“…The two 80:20 D 2 O/DMSO-d 6 samples were then pH-adjusted using dilute DCl and NaOD to yield one of the uncharged species, i.e., the carboxylic acid, at pH 2.11 and one of the carboxylate anion at pH 6.77.The concentration dependence of the 1 H chemical shifts was investigated by creating further samples in pure DMSO-d 6 from the stock solution with concentrations ranging from 100 μM to 50 mM. The absence of a concentration-dependent variation of chemical shifts indicates no substantial dimerization of furosemide in DMSO-d 6 solutions at the concentrations studied (see FigureS6).2.state NMR experiments were performed on a Bruker Avance III spectrometer operating at a 1 H Larmor frequency of 500.13 MHz using a 5 mm QXI 1 H/ 13 C/ 15 N/19 F/ 2 H probe.Chemical shifts were measured for the uncharged form of furosemide in pure DMSO-d 6 and for both charged (pH 6.77) and uncharged (pH 2.11) forms in a largely aqueous environment (80:20 v/v D 2 O/DMSO-d 6…”

Dual-Mode Arginine Assay Based on the Conformation Switch of a Ferrocene-Grafted Polypeptide

“…The morphology and structure of polypeptide assemblies can be regulated by altering self-assembly conditions, molecular composition and architecture, − and the introduction of secondary components such as small molecules, polymers, and nanoparticles. − The integration of diphenylalanine nanoassemblies into the tissue scaffold can provide unbranched nanotubes with membrane-disrupting activity . Cooperative assembly of peptide and silk fibroin into a nanofiber exhibited neural regeneration activity .…”