Manuel Cordova^1*, Pinelopi Moutzouri¹, Sten O. Nilsson Lill², Alexander Cousen³, Martin Kearns⁴, Stefan T. Norberg⁵, Anna Svensk Ankarberg⁵, James McCabe⁴, Arthur C. Pinon⁶, Staffan Schantz^5*, Lyndon Emsley^1*

1 Institut des Sciences et Ingénierie Chimiques, École Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland

2 Data Science & Modelling, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden

3 Early Chemical Development, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK

4 Early Product Development and Manufacturing, Pharmaceutical Sciences, R&D, AstraZeneca, Macclesfield, UK

5 Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden

6 Swedish NMR Center, Department of Chemistry and Molecular Biology, University of Gothenburg, 41390 Gothenburg, Sweden

* Corresponding authors emails: manuel.cordova@epfl.ch, Staffan.Schantz@astrazeneca.com, lyndon.emsley@epfl.ch

DOI10.24435/materialscloud:gk-51 [version v1]

Publication date: Jul 25, 2023

How to cite this record

Manuel Cordova, Pinelopi Moutzouri, Sten O. Nilsson Lill, Alexander Cousen, Martin Kearns, Stefan T. Norberg, Anna Svensk Ankarberg, James McCabe, Arthur C. Pinon, Staffan Schantz, Lyndon Emsley, Atomic-level structure determination of amorphous molecular solids by NMR, Materials Cloud Archive 2023.112 (2023), https://doi.org/10.24435/materialscloud:gk-51

Description

Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to both a high degree of overlap between measured signals, resulting in challenges for spectral assignment, and prevents the unambiguous identification of a single modelled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract preferred conformations and intermolecular interactions in the amorphous sample, and analyze the structure in terms of the hydrogen bonding and conformational factors that stabilize the amorphous form of the drug.

Materials Cloud sections using this data

Files

File name	Size	Description
Experimental_spectra.zip MD5md5:04e7c60965bbe65e0e750237f219d069	352.7 MiB	Raw NMR data of the experimental spectra measured.
MD_snapshots.zip MD5md5:9a06dc932a9f5ed69b44385709a020d6	1009.0 MiB	PDB files containing the snapshots extracted from the MD simulations of the amorphous sample.
ML_shifts.zip MD5md5:ee056fa2ad2795589cb72f549cfb4704	807.2 MiB	Numpy arrays containing the chemical shifts predicted using ShiftML2 on the MD snapshots.
Extracted_ftrs.zip MD5md5:a9d38f2637be6518d90c50c48deff74b	147.5 MiB	JSON files containing the geometric features extracted from the MD snapshots.
nmr_scoring.zip MD5md5:2d9793ed6466e9b85c481a0cd3040ec5	24.3 MiB	JSON and Numpy files containing the scores obtained for molecular environments from the MD snapshots to match the NMR experiments.
Random_structures.zip MD5md5:bcd751ddbfa38ca3f4473d719f0c21e3	286.3 MiB	XYZ files of 8000 randomly selected molecular environments from the MD snapshots. Each environment is represented by three files, "_cen" for the central molecule, "_env" for the neighbouring molecules, and "_all" for the complete environment.
Selected_structures.zip MD5md5:6de1b04f251372ecd04c61488ae1dd57	359.8 MiB	XYZ files of the 10107 NMR-selected molecular environments from the MD snapshots. Each environment is represented by three files, "_cen" for the central molecule, "_env" for the neighbouring molecules, and "_all" for the complete environment.
Random_structures_DFTB.zip MD5md5:3ec2bc600cc027c6cd52917269852980	302.3 MiB	Input and output files of the DFTB energy computation performed on the randomly selected molecular environments.
Selected_structures_DFTB.zip MD5md5:7e46d0dcc4c586fbc5992dd7e797d050	382.2 MiB	Input and output files of the DFTB energy computation performed on the NMR-selected molecular environments.
PDFs.zip MD5md5:99180a803cc551743fbd9f37aa4ac9ad	104.1 KiB	Raw data of the pairwise distribution function (PDF) measurements of the amorphous sample in Gudrun format.
Simulated_PDFs.zip MD5md5:39c3d62d68991fff67ba71e0e9caadbf	197.9 KiB	Numpy arrays containing the simulated pairwise distribution function (PDF) from the MD snapshots and NMR-selected molecular environments.
Clouds.zip MD5md5:de4eabc029244503d14788842b2cfff2	14.1 MiB	Interaction maps obtained for amorphous AZD4625
viz_structures.zip MD5md5:e4c9b99c14563c51381468570a1cf059	726.1 KiB	XYZ and VMD files used to visualize the structure of amorphous AZD4625.
Libraries.zip MD5md5:d1310ba236178bce8aed0c78613efc46	154.7 KiB	Python libraries necessary to run the analysis scripts.
Scripts.zip MD5md5:011a6d756c3b47465a810b43bb109c19	336.4 KiB	Jupyter notebooks containing the Python scripts used to analyse the data.

License

Files and data are licensed under the terms of the following license: Creative Commons Attribution Share Alike 4.0 International.
Metadata, except for email addresses, are licensed under the Creative Commons Attribution Share-Alike 4.0 International license.

External references

Keywords

MARVEL/DD1 NMR Amorphous solids machine learning molecular dynamics simulation structure determination