Rational Design of DNA Minor Groove-Binding Anti-Tumor Drugs

  • Richard E. Dickerson
  • Philip Pjura
  • Mary L. Kopka
  • David Goodsell
  • Chun Yoon
Part of the NATO ASI Series book series (NSSA, volume 126)


Many of the most useful antitumor drugs act by binding directly to double-helical DNA, interfering with both replication and transcription. Some of these drugs intercalate between adjacent base pairs. A second important class consists of those that bind within the minor groove of B-DNA. These latter tend to show a sequence specificity, binding best to regions of several successive A.T base pairs. We have embarked on a planned course of study of the molecular structures of complexes of such groove-binding drugs with synthetic DNA oligomers, with two goals: to understand the basis for sequence specificity, and to design new drug analogues that are capable of binding specifically to any desired base sequence. Such sequencereading molecules should be capable of being directed against key sequences typical of neoplastic rather than normal cells, or invader rather than host cells. If such molecules become a reality, they should have considerable importance in chemotherapy, directing their action against targeted cells and avoiding some of the more unpleasant side effects associated with chemotherapy.


Minor Groove Piperazine Ring Unpleasant Side Effect Bifurcate Hydrogen Bond Adjacent Base Pair 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    M. L. Kopka, P. Pjura, C. Yoon, D. Goodsell and R. E. Dickerson, The binding of netropsin to double-helical B-DNA, in “Structure and Motion: Membranes, Nucleic Acids and Proteins” E. Clementi, G. Corongiu, M. H. Sarma and R. H. Sarma, Eds., Adenine Press, New York (1985), p. 461.Google Scholar
  2. 2.
    M. L. Kopka, C. Yoon, D. Goodsell, P. Pjura and R. E. Dickerson, The molecular origin of DNA-drug specificity in netropsin and distamycin, Proc. Natl. Acad. Sci. USA 82:1376 (1985).PubMedCrossRefGoogle Scholar
  3. 3.
    M. L. Kopka, C. Yoon, D. Goodsell, P. Pjura and R. E. Dickerson, Binding of an antitumor drug to DNA: Netropsin and C-G-C-G-A-A-T-T- BrC-G-C-G. J. Mol. Biol. 183:553 (1985).PubMedCrossRefGoogle Scholar
  4. 4.
    H. R. Drew and R. E. Dickerson, Structure of a B-DNA dodecamer. III. Geometry of hydration. J. Mol. Biol. 151:535 (1981).PubMedCrossRefGoogle Scholar
  5. 5.
    M. L. Kopka, A. V. Fratini, H. R. Drew and R. E. Dickerson. Ordered water structure around a B-DNA dodecamer. J. Mol. Biol.163:129 (1983).PubMedCrossRefGoogle Scholar
  6. 6.
    D. J. Patcl, Antibiotic-DNA interactions: Intermolecular nuclear Overhauser effects in the netropsin-d(C-G-C-G-A-A-T-T-C-G-C-G) complex in solution. Proc. Natl. Acad. Sci. USA 17:6424 (1982).Google Scholar
  7. 7.
    M. H. Sarma, G. Gupta and R. H. Sarma, Netropsin specifically recognizes one of the two conformationally equivalent strands of poly(dA) •poly(dT). One dimensional nmr study at 500 MHz involving NOE transfer between netropsin and DNA protons. J. Biomol. Str. and Dyn. 2:1085 (1985).CrossRefGoogle Scholar
  8. 8.
    R. E. Dickerson and M. L. Kopka, Nuclear Overhauser data and stereochemical considerations suggest that netropsin binds symmetrically within the minor groove of poly(dA)•poly(dT), forming hydrogen bonds with both strands of the double helix. J. Biomol. Str. and Dyn. 2:submitted (1985).Google Scholar
  9. 9.
    R. S. Youngquist and P. B. Dervan, Sequence-specific recognition of B-DNA by oligo(N-methylpyrrolecarboxamide)s. Proc. Natl.Acad. Sci. USA 82:2565 (1985).PubMedCrossRefGoogle Scholar
  10. 10.
    K. D. Harshman and P. B. Dervan, Molecular recognition of B-DNA by Hoechst 33258. Nucl. Acids Res. 13:4825 (1985).PubMedCrossRefGoogle Scholar
  11. 11.
    R. Wing, H. Drew, T. Takano, C. Broka, S. Tanaka, K. Itakura and R. E. Dickerson, Crystal structure analysis of a complete turn of B-DNA. Nature 287:755 (1980).PubMedCrossRefGoogle Scholar
  12. 12.
    A. V. Fratini, M. L. Kopka, H. R. Drew and R. E. Dickerson. Reversible bending and helix geometry in a B-DNA dodecamer: CCGAATTBrCGCG. J.Biol.Chem.257:14686.Google Scholar
  13. 13.
    G. A. Jeffrey and J. Mitra, Three-center (bifurcated) hydrogen bonding in the crystal structures of amino acids. J. Am. Chem. Soc. 106:5546 (1984).CrossRefGoogle Scholar
  14. 14.
    D. Goodsell and R. E. Dickerson, Isohelical analysis of DNA groove- binding drugs. J. Med. Chem., submitted (1985).Google Scholar

Copyright information

© Springer Science+Business Media New York 1987

Authors and Affiliations

  • Richard E. Dickerson
    • 1
  • Philip Pjura
    • 1
  • Mary L. Kopka
    • 1
  • David Goodsell
    • 1
  • Chun Yoon
    • 1
  1. 1.Molecular Biology InstituteUniversity of California at Los AngelesLos AngelesUSA

Personalised recommendations