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

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  • Peter R. Spackman, University of Western Australia, University of Southampton
  • ,
  • Li Juan Yu, University of Western Australia, Australian National University
  • ,
  • Craig J. Morton, University of Melbourne
  • ,
  • Michael W. Parker, University of Melbourne, St Vincent’s Institute of Medical Research
  • ,
  • Charles S. Bond, University of Western Australia
  • ,
  • Mark A. Spackman, University of Western Australia
  • ,
  • Dylan Jayatilaka, University of Western Australia
  • ,
  • Sajesh P. Thomas

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
Pages (from-to)16780-16784
Number of pages5
Publication statusPublished - Nov 2019

    Research areas

  • crystal engineering, drug discovery, molecular recognition, noncovalent interactions, virtual screening

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