Session Speaker
Genome-Based Drug Design: Understanding
the Netropsin-DNA Interaction
Ya-Yin Fang, Vernon R. Morris, and William M. Southerland
The sequencing of the human genome has provided significant opportunities
to exploit DNA as a target in the rational design of therapeutic agents.
Netropsin has a strong preference for binding A/T rich regions of
DNA. In order to investigate the key factors responsible for DNA recognition
and binding by netropsin, molecular dynamics simulations were carried
out on a DNA-netropsin complex, in which two netropsin molecules are
bound to the palindromic inverted repeat, 16-mer: d(CTTAATTCGAATTAAG)2.
In this complex, the two netropsins are bound to the DNA minor groove
in a head to head orientation with the guanidinium-ends of both netropsins
pointed toward the center of the DNA. Molecular dynamics simulations
showed that the two netropsin molecules exhibited differences in RMS
behavior, binding energies, minor groove width fluctuations, and rotation
of netropsin structural planes. These observations suggest that small
molecule recognition and binding by DNA may be governed by mechanism(s)
that are much more complex than initially anticipated and may represent
unexpected challenges in genome-based drug design.
Acknowledgement: This work is supported by grant 2 G12 RR003048
from the National
Center for Research Resources, NIH
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