Desenvolvimento de um Modelo Empírico de Predição da Atividade de Inibidores da Urease utilizando o Método Semi-Empírico PM6

Abstract

Urease is an important enzyme for the research in agriculture, environment and medicine. This enzyme catalyzes the hydrolysis of urea to ammonia and carbamate, which decomposes spontaneously, yielding a second molecule of ammonia, causing a significant increase of pH solution. In order to develop theoretical models for the prediction of activities of urease inhibitors, we initially studied the enzyme’s spin multiplicity, which contains two Ni(II) íons, and the state of protonation of the oxygen located between the nickel ions. The results indicate that the system is best represented by the triplet or quintet state and the oxygen atom located between the nickel ions, probably is a hydroxyl ion. Based on these results, the construction of the models was based on literature proposals about the use of thermodynamic cycles for the calcultation of the free energy of binding between ligands and enzymes. In the present work, parameters such as the interaction enthalpy, the Gibbs free energy required for the inhibitor to go from the aqueous phase to the interior of the enzyme and the entropic losses associated to the freezing of bonds after the binding of the inhibitors to the enzyme were used to develop correlations with the measured experimental Ki values. The quantification of these parameters for some phosphinic acids derivatives from the literature allowed us to obtain a good empirical model for the correlation between experimental activity data and the theoretical parameters (r=0.92). The model was employed for the prediction of the relative activity of a series of new proposed compounds 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 urease inhibition profile by these compounds.