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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalAngewandte Chemie - International Edition
DOIs
Publication statusE-pub ahead of print - 6 Aug 2019

Fingerprint

Crystal engineering
Drug Discovery
Databases
Crystal structure
Crystals
Molecules
Proteins
Electrons
Ligands
Carrier concentration
Throughput

Cite this

@article{5baf88b6433a4add909df33ba1058f07,
title = "Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals",
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",
author = "Spackman, {Peter R.} and Yu, {Li Juan} and Morton, {Craig J.} and Parker, {Michael W.} and Bond, {Charles S.} and Spackman, {Mark A.} and Dylan Jayatilaka and Thomas, {Sajesh P.}",
year = "2019",
month = "8",
day = "6",
doi = "10.1002/anie.201906602",
language = "English",
journal = "Angewandte Chemie - International Edition",
issn = "1433-7851",
publisher = "Wiley-VCH Verlag GmbH & Co. KGaA",

}

Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals. / Spackman, Peter R.; Yu, Li Juan; Morton, Craig J.; Parker, Michael W.; Bond, Charles S.; Spackman, Mark A.; Jayatilaka, Dylan; Thomas, Sajesh P.

In: Angewandte Chemie - International Edition, 06.08.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Bridging Crystal Engineering and Drug Discovery by Utilizing Intermolecular Interactions and Molecular Shapes in Crystals

AU - Spackman, Peter R.

AU - Yu, Li Juan

AU - Morton, Craig J.

AU - Parker, Michael W.

AU - Bond, Charles S.

AU - Spackman, Mark A.

AU - Jayatilaka, Dylan

AU - Thomas, Sajesh P.

PY - 2019/8/6

Y1 - 2019/8/6

N2 - 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.

AB - 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.

KW - crystal engineering

KW - drug discovery

KW - molecular recognition

KW - noncovalent interactions

KW - virtual screening

UR - http://www.scopus.com/inward/record.url?scp=85070832680&partnerID=8YFLogxK

U2 - 10.1002/anie.201906602

DO - 10.1002/anie.201906602

M3 - Article

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

SN - 1433-7851

ER -