SUMO specific proteases (SENPs) are cysteine proteases that carry out the proteolytic processing of SUMO from its pro form as well as its deconjugation from substrate proteins. SENPs have been implicated in various cancers including prostate cancer, thyroid cancer and colon cancer. Therefore, the inhibition of SENPs is an attractive strategy for the treatment of cancer. However, the current SENP inhibitor development strategies target catalytic site and involve the usage of reactive functionalities to facilitate the covalent binding with a catalytic cysteine, which makes them less desirable for therapeutic purposes. Based on the available structural knowledge about the interaction of SENPs with various SUMO paralogues, an alternative approach for inhibiting SENPs could be via targeting SENP:SUMO protein-protein interaction. Here we have investigated the protein-protein interaction between SENP and SUMO as a target for structure based drug design using pocket prediction, ligand binding hotspot mapping, molecular dynamics simulation and in silico alanine mutagenesis. Finally, we have provided recommendations for the structure based design of SENP:SUMO protein-protein interaction inhibitors. Our study indicates that the SENP inhibitors targeting SENP:SUMO protein-protein interaction is a viable alternative strategy to existing inhibitors targeting the enzymatic site.