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Bridging crystal engineering and drug discovery by utilizing intermolecular interactions and molecular shapes in crystals

Bridging crystal engineering and drug discovery by utilizing intermolecular interactions and molecular shapes in crystals
Bridging crystal engineering and drug discovery by utilizing intermolecular interactions and molecular shapes in crystals

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.

crystal engineering, drug discovery, molecular recognition, noncovalent interactions, virtual screening
1433-7851
Spackman, Peter R.
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Yu, Li Juan
ecb5c296-a518-4928-a9bd-e0e88a1eae77
Morton, Craig J.
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Parker, Michael W.
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Bond, Charles S.
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Spackman, Mark A.
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Jayatilaka, Dylan
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Thomas, Sajesh P.
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Spackman, Peter R.
0b8d8f08-0b3b-45ce-8607-dafa10f28afe
Yu, Li Juan
ecb5c296-a518-4928-a9bd-e0e88a1eae77
Morton, Craig J.
0d8271ad-84f3-40ae-bc22-396fc14dbb39
Parker, Michael W.
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Bond, Charles S.
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Spackman, Mark A.
d685fdc8-3041-4ded-a93d-b043387d161a
Jayatilaka, Dylan
232438c0-5e8e-42cf-b319-8c4afdb8e86a
Thomas, Sajesh P.
ba2af856-5d9d-45f9-89aa-f27e67403d65

Spackman, Peter R., Yu, Li Juan, Morton, Craig J., Parker, Michael W., Bond, Charles S., Spackman, Mark A., Jayatilaka, Dylan and Thomas, Sajesh P. (2019) Bridging crystal engineering and drug discovery by utilizing intermolecular interactions and molecular shapes in crystals. Angewandte Chemie - International Edition. (doi:10.1002/anie.201906602).

Record type: Article

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.

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More information

e-pub ahead of print date: 6 August 2019
Keywords: crystal engineering, drug discovery, molecular recognition, noncovalent interactions, virtual screening

Identifiers

Local EPrints ID: 434839
URI: http://eprints.soton.ac.uk/id/eprint/434839
ISSN: 1433-7851
PURE UUID: 912f7608-6a8f-4299-af99-4a4bcefddd54

Catalogue record

Date deposited: 11 Oct 2019 16:30
Last modified: 16 Mar 2024 04:31

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Contributors

Author: Peter R. Spackman
Author: Li Juan Yu
Author: Craig J. Morton
Author: Michael W. Parker
Author: Charles S. Bond
Author: Mark A. Spackman
Author: Dylan Jayatilaka
Author: Sajesh P. Thomas

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