Abstract

Natural proteinaceous protease inhibitors inhibit through nonproductive binding to proteases and steric blockage of active sites. These complexes are among the most structurally complementary protein-protein interactions. To see if complementarity is correlated to activity, we scored the shape complementarity in 15 serine protease-inhibitor complexes through in silico docking and compared the scores against their reported inhibition constants (K_i). A statistically significant, moderate and positive correlation was observed between shape complementarity and K_i (R = 0.58; P = 0.023). We also analyzed other physicochemical factors involved in serine protease-inhibitor interactions for correlation, but no other factor was correlated to K_i. However, significant correlations were observed between hydrogen bonds and interface areas (R = 0.762; P = 0.0004); and between hydrophobic interactions and free energies of solvation (R = -0.634; P = 0.011).

Keywords: Peptidase inhibition, structure-activity correlation, structure complementarity.