Quantum Chemical Calculations on Locked Nucleic Acid based
Modifications: A Density Functional Theory (DFT) Study
Abstract
Antisense technology has been developed as the next generation drug
discovery methodology by which unwanted gene expression can be inhibited
by targeting mRNA specifically with antisense oligonucleotides. The
computational studies of antisense modifications based on
phosphorothioate (PS), methoxyethyl (MOE), locked nucleic acids (LNA)
may help to design better novel modifications. In the present study,
five novel LNA based modifications have been proposed. The
conformational search has been done to identify the most stable and
alternative stable conformations. The geometry optimization followed by
single point energy calculation has been done at B3LYP/6-31G(d,p) level
for gas phase and B3LYP/6-311G(d,p) level for the solvent phase for all
modifications at monomer as well as base pair level. The electronic
properties and the quantum chemical descriptors of the antisense
modifications were derived and compared. The local and global reactivity
descriptors, such as hardness, chemical potential, electronegativity,
electrophilicity index, Fukui function all were calculated at the DFT
level for the optimized geometries. A comparison of global reactivity
descriptors confirmed that LNA based modifications are the most reactive
modifications. They may form a stable duplex when bound to complementary
nucleotides, compared to other modifications. Therefore, we are
proposing that one of our proposed antisense modifications (A3) may show
strong binding to the complementary nucleotide as LNA and may also show
reduced toxic effects like MOE. The base pair studies may help us to
understand the extent to which our proposed modifications can form
standard Watson-Crick base pairing required for oligomer duplexes. This
computational approach may be very useful to propose novel modifications
prior to undergoing synthesis experimentally in the area of antisense or
RNAi technology.