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Finding potential DNA-binding compounds by using molecular shape

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Summary

For the first time a general shape-search docking algorithm (DOCK) has been applied to the minor and major grooves of A-, B- and Z-type DNA dodecamers and to an intercalation site in a B-DNA-type hexamer. Both experimentally and theoretically derived geometries for the various DNA fragments were used. The DOCK searches were carried out on a subset of the Cambridge Crystallographic Database, consisting of almost 10 000 molecules. One of the molecules that scored best in terms of the DOCK algorithm was CC-1065, a potent antitumor agent known to (covalently) bind the AT-rich parts of the minor groove of B-DNA. Several known DNA-binding agents also scored highly. Molecules with shapes complementary to A-, B- and Z-type DNA were indicated by DOCK. In addition, compounds were extracted from the database that might be selective for the GC-rich regions of the minor groove of B-DNA. Many of the compounds in the present study may serve as a starting point for further molecular design of novel DNA-binding ligands.

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Author notes

  1. Peter D. J. Grootenhuis

    Present address: Organon International, P.O. Box 20, NL-5340 BH, Oss, The Netherlands

Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, University of California, 94143-0446, San Francisco, CA, U.S.A.

    Peter D. J. Grootenhuis, Diana C. Roe, Peter A. Kollman & Irwin D. Kuntz

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  1. Peter D. J. Grootenhuis
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  2. Diana C. Roe
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  3. Peter A. Kollman
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  4. Irwin D. Kuntz
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Grootenhuis, P.D.J., Roe, D.C., Kollman, P.A. et al. Finding potential DNA-binding compounds by using molecular shape. J Computer-Aided Mol Des 8, 731–750 (1994). https://doi.org/10.1007/BF00124018

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  • DOI: https://doi.org/10.1007/BF00124018

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