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.