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Atomic-level structure of the amorphous drug Atuliflapon via NMR crystallography

Jacob Holmes1,2, Daria Torodii1, Martins Balodis1, Manuel Cordova1,2, Albert Hofstetter1, Federico Paruzzo1, Sten Nilsson Lill3, Emma Eriksson3, Pierrick Berruyer1, Bruno Simões de Almeida1, Mike Quayle4, Stefan Norberg4, Anna Svensk Ankarberg4, Staffan Schantz4, Lyndon Emsley1,2*

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

2 National Centre for Computational Design and Discovery of Novel Materials MARVEL, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.

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

4 Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Gothenburg, Sweden.

* Corresponding authors emails: lyndon.emsley@epfl.ch
DOI10.24435/materialscloud:9r-b9 [version v1]

Publication date: Jan 28, 2025

How to cite this record

Jacob Holmes, Daria Torodii, Martins Balodis, Manuel Cordova, Albert Hofstetter, Federico Paruzzo, Sten Nilsson Lill, Emma Eriksson, Pierrick Berruyer, Bruno Simões de Almeida, Mike Quayle, Stefan Norberg, Anna Svensk Ankarberg, Staffan Schantz, Lyndon Emsley, Atomic-level structure of the amorphous drug Atuliflapon via NMR crystallography, Materials Cloud Archive 2025.22 (2025), https://doi.org/10.24435/materialscloud:9r-b9

Description

We determine the complete atomic-level structure of the amorphous form of the drug atuliflapon, a 5-lipooxygenase activating protein (FLAP) inhibitor, via chemical-shift-driven NMR crystallography. The ensemble of preferred structures allows us to identify a number of specific conformations and interactions that stabilize the amorphous structure. These include preferred hydrogen-bonding motifs with water and with other drug molecules, as well as conformations of the cyclohexane and pyrazole rings that stabilize structure by indirectly allowing for optimization of hydrogen bonding.

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Files

File name Size Description
DFTB_clusters_random.zip
MD5md5:6e097b33710eea67a46e02778a3a5b5d
532.5 MiB DFTB input/output for random clusters
clusters_random.zip
MD5md5:aa925bc3b681aca66238eaa42f02e339
105.4 MiB randomly selected clusters from the MD set
interaction_maps_ref.zip
MD5md5:36765700b0c1efda346d750d541c0889
117.5 MiB 3D atomic density maps
ML_shifts.zip
MD5md5:dd10a23dc64fed0361568015ed2ce094
2.4 GiB Chemical shift predictions using ShiftML2
nmr_scoring_ref.zip
MD5md5:c8adb6cf5faf00559ae3320777efedd3
1.2 GiB P-value score for each chemical environment
NMR_Experiments.zip
MD5md5:51cf1a14b077222915b89908397d9041
444.9 MiB NMR data for crystalline and amorphous formulations
nmr_scoring_ref_N6_W3.zip
MD5md5:0194cb8f7d38c382645eebba170f4afa
214.9 MiB p-value for each chemical environment using local atomic sites
DFTB_clusters_selected.zip
MD5md5:432b355588ea40afae24698d41ecd77c
1.5 GiB DFTB input/output for clusters from the NMR set
clusters_selected.zip
MD5md5:58ae0be210aa21983b3cfd0608e83e82
226.5 MiB clusters from the NMR set
MD-snapshots.zip
MD5md5:1d74be6223c4956b4eeb016e8a0cf9f6
3.1 GiB Molecular Dynamics Simulations
SI README.rtf
MD5md5:a5b6ab973b15d808b76675008de8f65c
2.3 KiB Readme for SI material labeled by folder name

License

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

External references

Journal reference (Paper with previously published which contains NMR data, MD simulations, and crystalline assignment)
Cordova, M., Balodis, M., Hofstetter, A., Paruzzo, F., Nilsson Lill, S. O., Eriksson, E. S. E., Berruyer, P., Simões de Almeida, B., Quayle, M. J., Norberg, S. T., Svensk Ankarberg, A., Schantz, S., & Emsley, L. Nature communications, 12(1), 2964. (2021). doi:10.1038/s41467-021-23208-7
Journal reference (External reference to the paper)
J. Holmes, D. Torodii, M. Balodis, M. Cordova, A. Hofstetter, F. Paruzzo, S. Nilsson Lill, P. Berruyer, B. Simoes de Almeida, M. Quayle, S. Norberg, A. Ankarberg, S. Schantz, L. Emsley, Faraday Discuss, 255 , 342-354, 2025 doi:10.1039/d4fd00078a

Keywords

Solid-State NMR NMR Crystallography Atuliflapon

Version history:

2025.22 (version v1) [This version] Jan 28, 2025 DOI10.24435/materialscloud:9r-b9