Exploring ensembles of bioactive or virtual analogs of X-ray ligands for shape similarity searching

Abstract

Shape similarity searching is a popular approach for ligand-based virtual screening on the basis of three-dimensional reference compounds. It is generally thought that well-defined experimentally determined binding modes of active reference compounds provide the best possible basis for shape searching. Herein, we show that experimental binding modes are not essential for successful shape similarity searching. Furthermore, we show that ensembles of analogs of X-ray ligands—in the absence of these ligands—further improve the search performance of single crystallographic reference compounds. This is even the case if ensembles of virtually generated analogs are used whose activity status is unknown. Taken together, the results of our study indicate that analog ensembles representing fuzzy reference states are effective starting points for shape similarity searching.

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Acknowledgements

We thank the OpenEye Scientific Software, Inc., for providing a free academic license of the OpenEye chemistry toolkit and the ROCS program.

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Correspondence to Jürgen Bajorath.

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Miyao, T., Bajorath, J. Exploring ensembles of bioactive or virtual analogs of X-ray ligands for shape similarity searching. J Comput Aided Mol Des 32, 759–767 (2018). https://doi.org/10.1007/s10822-018-0128-8

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Keywords

  • Shape similarity searching
  • ROCS
  • X-ray ligands
  • Analogs
  • Conformational ensembles
  • Fuzzy reference states