Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

doi:10.1002/anie.201906602

. 2019 Nov 18;58(47):16780-16784.

doi: 10.1002/anie.201906602. Epub 2019 Aug 19.

Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

Peter R Spackman^{1

2}, Li-Juan Yu^{1

3}, Craig J Morton⁴, Michael W Parker^{4

5}, Charles S Bond¹, Mark A Spackman¹, Dylan Jayatilaka¹, Sajesh P Thomas^{1

6}

Affiliations

¹ School of Molecular Sciences, University of Western Australia, Perth, WA, 6009, Australia.
² School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
³ Research School of Chemistry, Australian National University, Canberra, Australia.
⁴ Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
⁵ St Vincent's Institute of Medical Research, Fitz-roy, VIC, 3065, Australia.
⁶ Department of Chemistry and iNano, Aarhus University, Langelandsgade 140, Aarhus, 8000, Denmark.

PMID: 31385643
DOI: 10.1002/anie.201906602

Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

Peter R Spackman et al. Angew Chem Int Ed Engl. 2019.

. 2019 Nov 18;58(47):16780-16784.

doi: 10.1002/anie.201906602. Epub 2019 Aug 19.

Authors

Peter R Spackman^{1

2}, Li-Juan Yu^{1

3}, Craig J Morton⁴, Michael W Parker^{4

5}, Charles S Bond¹, Mark A Spackman¹, Dylan Jayatilaka¹, Sajesh P Thomas^{1

6}

Affiliations

¹ School of Molecular Sciences, University of Western Australia, Perth, WA, 6009, Australia.
² School of Chemistry, University of Southampton, Highfield, Southampton, SO17 1BJ, UK.
³ Research School of Chemistry, Australian National University, Canberra, Australia.
⁴ Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, VIC, 3010, Australia.
⁵ St Vincent's Institute of Medical Research, Fitz-roy, VIC, 3065, Australia.
⁶ Department of Chemistry and iNano, Aarhus University, Langelandsgade 140, Aarhus, 8000, Denmark.

PMID: 31385643
DOI: 10.1002/anie.201906602

Abstract

Most structure-based drug discovery methods utilize crystal structures of receptor proteins. Crystal engineering, on the other hand, utilizes the wealth of chemical information inherent in small-molecule crystal structures in the Cambridge Structural Database (CSD). We show that the interaction surfaces and shapes of molecules in experimentally determined small-molecule crystal structures can serve as effective tools in drug discovery. Our description of the shape and interaction propensities of molecules in their crystal structures can be used to screen them for specific binding compatibility with protein targets, as demonstrated through the high-throughput profiling of around 138 000 small-molecule structures in the CSD and a series of drug-protein crystal structures. Electron-density-based intermolecular boundary surfaces in small-molecule crystal structures and in target-protein pockets are utilized to identify potential ligand molecules from the CSD based on 3D shape and intermolecular interaction matching.

Keywords: crystal engineering; drug discovery; molecular recognition; noncovalent interactions; virtual screening.

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References

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1. A. Lavecchia, C. Di Giovanni, Curr. Med. Chem. 2013, 20, 2839-2860.
1. None
1. A. Nicholls, G. B. McGaughey, R. P. Sheridan, A. C. Good, G. Warren, M. Mathieu, S. W. Muchmore, S. P. Brown, J. A. Grant, J. A. Haigh, N. Nevins, A. N. Jain, B. Kelley, J. Med. Chem. 2010, 53, 3862-3886;
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[1] E. Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985-2993.

[2] E. Fischer, Ber. Dtsch. Chem. Ges. 1894, 27, 2985-2993.

[3] A. Lavecchia, C. Di Giovanni, Curr. Med. Chem. 2013, 20, 2839-2860.

[4] A. Lavecchia, C. Di Giovanni, Curr. Med. Chem. 2013, 20, 2839-2860.

[5] None

[6] None

[7] A. Nicholls, G. B. McGaughey, R. P. Sheridan, A. C. Good, G. Warren, M. Mathieu, S. W. Muchmore, S. P. Brown, J. A. Grant, J. A. Haigh, N. Nevins, A. N. Jain, B. Kelley, J. Med. Chem. 2010, 53, 3862-3886;

[8] A. Nicholls, G. B. McGaughey, R. P. Sheridan, A. C. Good, G. Warren, M. Mathieu, S. W. Muchmore, S. P. Brown, J. A. Grant, J. A. Haigh, N. Nevins, A. N. Jain, B. Kelley, J. Med. Chem. 2010, 53, 3862-3886;

[9] G. M. Sastry, S. L. Dixon, W. Sherman, J. Chem. Inf. Model. 2011, 51, 2455-2466;

[10] G. M. Sastry, S. L. Dixon, W. Sherman, J. Chem. Inf. Model. 2011, 51, 2455-2466;

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Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

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Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

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