ABSTRACT The inhibition activity of (2S)-cyanopyrrolidine analogues for dipeptidyl peptidase IV has been quantitatively analyzed in terms of topological 0D-, 1D- and 2D-descriptors based on molecular graph theory. Statistically sound models have been obtained between the activity and various DRAGON descriptors through combinatorial protocol-multiple linear regression (CP-MLR) computational procedure. Amongst the large number of such derived models, the most significant ones have only been discussed to draw meaningful conclusions. Additionally the inhibition activity for DPP8 enzyme, reported for a limited number of such congeners, has also been correlated with such descriptors. From the final statistically significant models, it appeared that the mode of actions of titled compounds were different for DPP IV and DPP8 enzyme systems. Applicability domain analysis carried out for DPP IV inhibitors revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data and all of the compounds was within the applicability domain of the proposed model and were evaluated correctly.