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The quest for bioisosteric replacements.

Markus Wagener1, Jos P M Lommerse

  • 1NV Organon, Department of Molecular Design and Informatics, P.O. Box 20, 5340BH Oss, The Netherlands. markus.wagener@organon.com

Journal of Chemical Information and Modeling
|March 28, 2006
PubMed
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A new search method identifies bioisosteric replacements for drug discovery using topological pharmacophore fingerprints. This validated approach aids researchers in finding suitable molecular fragments from large databases.

Area of Science:

  • Medicinal Chemistry
  • Computational Chemistry
  • Drug Discovery

Background:

  • Advancing drug discovery requires efficient methods to identify bioisosteric replacements.
  • Existing methods may lack the precision needed for large-scale fragment screening.

Purpose of the Study:

  • To present a novel and validated search method for retrieving potential bioisosteric replacements.
  • To improve the efficiency of drug discovery projects through fragment-based searching.

Main Methods:

  • Development of an optimized topological pharmacophore fingerprint incorporating weighted descriptors.
  • Utilizing Euclidean distance for comparing fingerprints in a database of over 700,000 structural fragments.
  • Validation using over 2200 bioisosteric fragment pairs from the BIOSTER database.

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Main Results:

  • The search method demonstrated excellent separation between true bioisosteric pairs and random fragments.
  • High performance was observed for R-group fragments (2.2 SD units), linkers (2.6 SD units), and cores (2.6 SD units).
  • The method was implemented as the IBIS intranet application, now used by Organon researchers.

Conclusions:

  • The topological pharmacophore fingerprint-based search method is effective for identifying bioisosteric replacements.
  • This approach significantly enhances the ability to screen large fragment databases for drug discovery.
  • The IBIS application provides a valuable tool for routine use in pharmaceutical research.