Cardiac glycosides, well established therapeutics for treatment of cardiac diseases, have been nowadays subjected to drug repositioning due to their anticancer potential. Their main mode of action is inhibition of Na+/K+-ATPase (NKA) which leads to cell apoptosis, a major cause of their cytotoxic properties. However, NKA is present in both cancer and healthy cells, therefore, its inhibition can lead to severe side effects. One of such potential inhibitors is a cardiac glycoside hyrcanoside (Hyr). Hyr contains a carbonyl group C-19, which is probably crucial for NKA binding. Thus a chemical modification of this group by compounds containing an oxime bond could lead to suppression of Hyr ability to bind NKA due to steric hindrance. An oxime bond is unstable at lower pH values, therefore, it is used for conjugations of compounds, for which release at such pH is desired. Based on this, the aim of this work was to design pH-sensitive Hyr derivatives with an oxime bond and to perform in silico simulations of their complexes with NKA. Using molecular docking, our results indicate that modification of C-19 carbonyl leads to loss of Hyr ability to bind to NKA. In the next part of this study, our knowledge of Hyr-NKA complexes will be extended by performing simulations in real-time using molecular dynamics. We believe that a modification of Hyr C-19 carbonyl containing an oxime bond will enhance ability of Hyr to selectively kill cancer cells and that the Hyr conjugates could have a potential to be used in a cancer therapy.