Journal of Cheminformatics

, 3:P37 | Cite as

Extraction of useful bioisostere replacments from the PDB

  • T Ritschel
  • DJ Wood
  • J de Vlieg
  • M Wagener
Open Access
Poster presentation


Resource Requirement Structure Database Similar Protein Optimal Balance Replacement Study 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Bioisosteres are defined as structurally different molecules or substructures that can form similar intermolecular interactions, and therefore fragments that bind to similar protein pocket can be considered to have exhibited a degree of bioisosterism [1, 2]. In this work a new method for the calculation of localized binding site similarities based on 3D-pharmacophore fingerprints is presented. The method needs no prior, time-consuming alignment of the proteins and therefore an on-the-fly searching of PDB scale crystal structure database for potential bioisosteric replacements is feasible. The binding site fingerprints are experimentally optimized to improve their performance. A variety of attributes of the fingerprints were considered in the optimization, including the placement of pharmacophore features, whether or not the fingerprints were fuzzified, and the resolution and complexity of the pharmacophore fingerprints (2-, 3- and 4-point fingerprints). Finally, fuzzy 3-point pharmacophore fingerprints were chosen to represent the optimal balance between computational resource requirements and the identification of potential replacements, and were therefore used to represent the localized binding sites in a searchable fragment database.

The utility of the approach is demonstrated by (i) separating known similar binding site pairs from random binding site pairs and (ii) a bioisosteric replacement study for fragments binding to subpockets of different proteins.


  1. 1.
    Lima LM, Barreiro EJ: Bioisosterism: A Useful Strategy for Molecular Modification and Drug Design. Curr Med Chem. 2005, 12: 23-49.CrossRefGoogle Scholar
  2. 2.
    Kennewell EA, Willet P, Ducrot P, Luttmann C: Identification of Target-Specific Bioisosteric Fragments from Ligand–Protein Crystallographic Data. J Comp Aided Mol Des. 2006, 20: 385-394. 10.1007/s10822-006-9072-0.CrossRefGoogle Scholar

Copyright information

© Ritschel et al; licensee BioMed Central Ltd. 2011

This article is published under license to BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Authors and Affiliations

  1. 1.Computational Drug Discovery Group, Center for Molecular and Biomolecular InformaticsRadboud University Nijmegen Medical CentreNijmegenThe Netherlands
  2. 2.Molecular Design & Informatics, MSDOssThe Netherlands

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