Investigation of the Factors That Dictate the Preferred Orientation of Lexitropsins in the Minor Groove of DNA

Lexitropsins are
small molecules that bind to the minor groove
of DNA as antiparallel dimers in a specific orientation. These molecules
have shown therapeutic potential in the treatment of several diseases;
however, the development of these molecules to target particular genes
requires revealing the factors that dictate their preferred orientation
in the minor grooves, which to date have not been investigated. In
this study, a distinct structure (thzC) was carefully designed as
an analog of a well-characterized lexitropsin (thzA) to reveal the
factors that dictate the preferred binding orientation. Comparative
evaluations of the biophysical and molecular modeling results of both
compounds showed that the position of the dimethylaminopropyl group
and the orientation of the amide links of the ligand with respect
to the 5′–3′-ends; dictate the preferred orientation
of lexitropsins in the minor grooves. These findings could be useful
in the design of novel lexitropsins to selectively target specific
genes.