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Identification of target-specific bioisosteric fragments from ligand–protein crystallographic data

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Abstract

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand–protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure.

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Author notes

  1. Elizabeth A. Kennewell

    Present address: Health Informatics Service, Sheffield West Primary Care Trust, Sheffield, S10 3TG, UK

Authors and Affiliations

  1. Krebs Institute of Biomolecular Research and Department of Information Studies, University of Sheffield, Sheffield, S1 4DP, UK

    Elizabeth A. Kennewell & Peter Willett

  2. Chemical Sciences, Sanofi-Aventis, 94400, Vitry-sur-Seine, France

    Pierre Ducrot & Claude Luttmann

Authors
  1. Elizabeth A. Kennewell
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  2. Peter Willett
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  3. Pierre Ducrot
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  4. Claude Luttmann
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Corresponding author

Correspondence to Peter Willett.

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Kennewell, E.A., Willett, P., Ducrot, P. et al. Identification of target-specific bioisosteric fragments from ligand–protein crystallographic data. J Comput Aided Mol Des 20, 385–394 (2006). https://doi.org/10.1007/s10822-006-9072-0

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  • DOI: https://doi.org/10.1007/s10822-006-9072-0

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