The inhibition of calcineurin-NFAT signaling by blocking protein-protein interaction with N-(4-oxo-1(4H)-naphthalenylidene)benzenesulfonamide analogues was studied in order to obtain mechanistic information about the effects of structural modification and molecular design of immunomodulation agents. The study was carried out by quantitative structure-activity relationship (QSAR) analysis using 2D-QSAR and hologram QSAR (HQSAR) methods. The statistical results of the two models showed the best prediction and fitness ($r^2>0.900$) for the inhibition activities. The inhibitory activities from the 2D-QSAR models were dependent upon the electronic affinity of electron acceptor and optimum dipole moment ($DM_{opt}.=4.491$ Debye). In addition, the HQSAR model provided information about which structural distinctions could be significant contributors the inhibition.