Context <p>Many small organoselenium compounds, such as substituted diselenides, mimic the glutathione peroxidase (GPx) activity by catalysing the reduction of hydrogen peroxide. In this context, the effect of substitution in di-2(N-cyclohexyl,N-(methylamino)-methyl)phenyl diselenide (CMP) on its GPx-like activity (to reduce hydrogen peroxide) has been investigated using the density functional theory. It was observed that the presence of an electron donating group as well as secondary amino group (instead of tertiary one) favoured the peroxide reduction process, which is consistent with the experimental reports. This study revealed that the presence of electron donating group lowers the energy requirement for distortion in zwitterion of the selenol during the progress of the reaction, thereby enhancing its catalytic activity.</p> Methods <p>Geometry optimizations, Natural Bond Order (NBO) and the wavefunction calculations were carried out using Gaussian16 software at B3PW91/6–31+G(d,p) level of theory. Improved energy calculations were carried out at B3PW91/6–311++ G(3df,3pd)//B3PW91/6–31+G(d,p) level of theory. The solvent effect was modelled using the self-consistent reaction field (SCRF) method utilizing polarizable continuum model (PCM). Activation Strain Model was used to study the contributions of the steric and electronic effects due to substitutions. Wavefunction analysis was carried out using <i>Multiwfn</i>&#xa0;software.</p>