Desenvolvimento de um modelo empírico de predição da atividade de inibidores da esterol 14a-desmetilase (CYP51) utilizando o método semiempírico PM6

Abstract

The enzyme sterol 14a-demethylase (CYP51) is one of the major targets for the design of new fungicides. The CYP51 inhibitors or demethylase inhibitors (DMIs) act by interruption of ergosterol biosynthesis and, as a consequence, of fungi growth. The DMIs bind to the enzyme active site by means of a coordinative bond to the iron atom of the enzyme heme group. In the present work, a chimeric substitution model of the phytopathogenic fungus Mycosphaerella graminicola CYP51 was constructed based on the crystallographic structure of the Mycobacterium tuberculosis CYP51. Based on this model, the interaction enthalpies of a series of triazolic fungicides was obtained with the semiempirical molecular orbital model PM6. It was observed that the interaction enthalpy, the water solubility and the entropic losses associated to the freezing of bonds after the binding of the inhibitors to the enzyme are important parameters for the design of new DMIs. It was possible to obtain a good empirical model for the correlation between experimental activity data and the theoretical parameters of triazolic DMIs (r=0.94, SD=0.63). The model was employed for the prediction of the relative activity of a series of new proposed fungicides synthetised by the organophosphorous synthesis group of UFRRJ. It was possible to identify which compounds are the most promising and which are the main factors that should be modified in order to optimize the inhibition profile of CYP51, such as the number of rotatable bonds frozen after the binding to the enzyme active site.