Quantum Chemical Calculations on Locked Nucleic Acid based Antisense Modifications: A Density Functional Theory (DFT) Study at Monomer Level

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. It has been observed that a good number of these molecules entered into clinical trials at a faster rate and some of them got approved. 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, newer LNA based modifications have been proposed. The conformational search and density functional theory (DFT) calculations have been used to investigate the quantum chemical parameters of PS, LNA, MOE, and novel LNA based proposed modifications. The conformational search has been done to identify the most 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 of all modifications. The electronic properties and the quantum chemical descriptors for the frontier molecular orbitals of all the antisense modifications were derived and compared. The local and global reactivity descriptors, such as hardness, chemical potential, electronegativity, electrophilicity index, Fukui function calculated at DFT level for the optimized geometries. These are used for understanding the reactive nature and reactive sites of the modifications. A comparison of global reactivity descriptors confirmed that LNA based modifications are the most reactive modifications and prone to the chemical reactions. It may form stable duplex when it is bound to complementary nucleotides, compared to other modifications. Therefore, we are proposing that one of our proposed antisense modification (A3) may show strong binding to the complementary nucleotide as LNA and may also show reduced toxic effects like MOE.