The principle of antisense technologies is based on the specific inhibition of unwanted gene expression by blocking mRNA activity. A rapid increase in the number of antisense molecules in clinical trials was observed. The 2′-O-methoxyethyl modification (MOE) showed a good safety profile with limited binding affinity, whereas locked nucleic acid (LNA) showed high potency by exhibiting strong binding affinity and high toxicity. The novel 2′-4′ conformationally restricted nucleoside analogue has the structural features of both MOE (second generation) and LNA (third generation). It is possible to acquire the positive features of both MOE and LNA and show high potency without an increase in the hepatotoxicity. Structural insight at the monomer level can be useful in understanding the function of the modification and designing derivatives of these molecules. Therefore, the quantum chemical studies of the antisense nucleoside modifications like MOE, LNA, and two stereo isomers of constrained MOE (cMOE) were performed at the monomer level. The conformational preferences of these antisense monomers were studied using a multidimensional conformational search. The semiempirical method PM6 of the MOPAC software was used for the conformational search. Three structures were chosen based upon energy criteria after the conformational search for all the monomers. Full geometry optimization calculations were done on the three structures (most stable, alternate stable, start structures) of all the monomers using the Hartree–Fock method. This was followed by single-point density functional theory (DFT) calculations in gas phase and solvent phase using the B3LYP/6-311G** basis set. Quantum chemical descriptors were derived for the stable geometries of all these monomers. Structural properties and reactivity descriptors of all four antisense modifications in the gas phase and the solvent phase were also studied. The results suggest that LNA is more reactive, that is, highly toxic in nature and with a good binding affinity, while MOE is less reactive, that is, less toxic with weak binding affinity. These results agree with the experimental findings. Properties of 2′-4′ conformationally restricted modifications (ScMOE and RcMOE) showed better stability than MOE and less reactivity than LNA. Therefore, these cMOEs may show less toxicity with high binding affinity toward the target, as shown in the experiments. Study at the monomer level would help in understanding the conformational flexibility available with all modifications, along with various reactivity descriptors, which may help guide the design of new modifications. This study attempts to find an indirect relationship between the quantum chemical descriptors and the experimental data, which may be useful in designing new molecules or modifications tuned for specific requirements of antisense molecules. © 2013 Wiley Periodicals, Inc.