4A). On the other hand, the presence of Wortmannin the inhibitors did not induce any alteration in KM values ( Fig. 4B). The KM values were around 740 μM ( Table 1). In addition, the inhibition constant values (KI) were between 0.075 and 9.240 μM ( Table 1). KI reflects the dissociation of enzyme-inhibitor and the smaller its value, the greater its ability to bind the inhibitor, which can be observed that Lac01 and Lac02 presented the best capacity to inhibit the enzymatic activity of PLA2 from B. jararacussu, while Lac05–Lac08 presented low inhibition capacity ( Fig. 4).

This set of results shows that the enzymatic inhibition provoked by lactone derivatives is non-competitive and that these compounds might be bound to a site different from that of the enzyme active site and do not compete with HPGP. The structures of the sesquiterpene lactone derivative compounds were submitted to quantum chemistry calculations and chemometric studies (PCA and HCA). PCA (Principal Components Analyze) is a multivariate statistical technique that reduces the data

dimensionality by the linear transformation of the original data set in a new and smaller set of uncorrelated variables (Beebe and Pell, 1988). This technique has been widely applied in the chemometric studies of bioactive compounds (Da Silva et al., 2004, Weber et al., 2005 and Calgarotto et al., 2007). Fisher weight was used to analyze the

auto-scaled values for all the calculated properties (molecular, electronic and topological). Fisher weight revealed six descriptors, whose variances may be responsible for the Selleckchem Inhibitor Library differences observed in the biological activities of the sesquiterpene lactone derivative compounds indicated (HOMO, VOL, GAP, IP, Log P, Balaban-type index from polarizability weighted distance matrix). The chemometric analyses used these six descriptors, selected by Fisher weight. When the PCA technique was applied to the auto-scaled values of the selected properties obtained from the ab initio quantum calculations (DFT – UB3LYP/6-31G*) of the lactone compounds, the best separation was obtained using the values of three variables (VOL, Log P, HOMO energy) ( Fig. 5A). Fig. 5B shows Diflunisal that, utilizing values of proprieties selected by PCA (VOL, Log P, HOMO energy), all sesquiterpene lactone derivative compounds may be grouped in three distinct regions: Group 1 (Lac01–Lac02, high activity in all tests); Group 2 (Lac03–Lac04, intermediate activity in all tests); Group 3 (Lac05–Lac08, low (or no) activity in all tests). PCA results showed that the first component (PC1) is responsible for 75.78% of the data variance and that the second one (PC2) is responsible for 22.29% (data not shown). Considering the first and second principal components (PC1 and PC2), the accumulated variance increased to 98.07%.