4. Conclusions
In the present work, we have used semi empirical and DFT based methods
to study the structure, stability and reactivity descriptors of standard
antisense molecules along with the proposed novel antisense
modifications at monomer and base pair level. We have calculated the
geometrical parameters and frontier orbital energies for different
antisense modifications both in the gas phase and the solvent phase. One
goal of the study was to identify the global reactivity descriptors that
could be used in recognizing the chemically reactive and stable
molecules, the second was to identify the local reactivity descriptors
that could be used in determining the chemically more reactive sites in
each modification. From the whole study and the results presented in
this contribution, it has been demonstrated that the reactive sites of
interaction of all the antisense modifications can be predicted by using
DFT-based global reactivity descriptors as well as Fukui-function
calculations. A comparison of global reactivity descriptors confirmed
that LNA based modifications LCC, LCS, and A3 are most reactive
modifications and prone to chemical reactions and may form stable
duplexes when bound to complementary nucleotides, compared to other
modifications. Theoretical results from reactivity descriptors show that
C1’ is a more reactive site for nucleophilic, electrophilic and free
radical attacks in all LNA based modifications except A3 modification.
In the novel proposed modifications A3 was showing similar kinds of
properties with LCC and LCS. The A3 modification was also showing closer
values of properties with CME and CMS which are claimed to be less toxic
modifications. Therefore, A3 antisense modification may also strongly
bind to the complementary nucleotides as LNA and may show reduced toxic
effects. The base pair studies may help us to understand the extent to
which our proposed modifications are stable and capable of complementary
base pairing required to form oligomer duplexes. This computational
approach using quantum chemical methods may be very useful to propose
better modifications than the existing ones before performing the
experiments in the area of antisense or RNAi technology. However, the
molecular dynamics simulation study by incorporating these modifications
in a duplex form can throw more light and that will be the continuation
of this work.