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Shape-selective recognition of a model Okazaki fragment by geometrically-constrained bis-distamycins

W H Gmeiner1, W Cui, D E Konerding

  • 1Eppley Institute, Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha 68198-6805, USA. bgmeiner@unmc.edu

Journal of Biomolecular Structure & Dynamics
|January 15, 2000
PubMed

Insights

Bis-distamycins targeting Okazaki fragments show promise as anticancer drugs. Specifically, para-configured bis-distamycins bind tightly to the Okazaki fragment minor groove, suggesting a potential therapeutic strategy.

Area of Science:

  • Medicinal Chemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Okazaki fragments are crucial in DNA replication and elevated in cancers.
  • Structural studies reveal a bend at the junction region (JR) of Okazaki fragments.
  • This unique structure presents a potential target for anticancer drug design.

Purpose of the Study:

  • To identify structural motifs that bind to the Okazaki fragment minor groove.
  • To investigate the binding of geometrically-constrained bis-distamycins to model Okazaki fragments.
  • To explore the potential of bis-distamycins as anticancer agents.

Main Methods:

  • Synthesis and selection of six bis-distamycins with varying configurations.
  • Gel-shift assays and deltaT(M) measurements to determine binding affinity (Kd).
  • Molecular modeling to elucidate the binding complex structure.

Main Results:

  • Para-configured bis-distamycins demonstrated tight binding to the model Okazaki fragment (Kd ~10^-6 to 10^-8 M).
  • Meta-oriented bis-distamycins and mono-distamycins showed no significant binding.
  • Molecular modeling revealed an S-shaped conformation of a para bis-distamycin (MT-9) fitting the minor groove.

Conclusions:

  • Para-configured bis-distamycins are effective binders to the Okazaki fragment minor groove.
  • The specific geometry of para bis-distamycins is critical for binding.
  • These findings support the development of bis-distamycin derivatives as novel anticancer therapeutics targeting DNA replication.

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