Estudo teórico da relação estrutura atividade da piperina e seus análogos à inibição do citocromo P450 hepático

Abstract

Some piperine (Piper nigrum) analogous derivatives are able to inhibit the action of the hepatic enzymes that metabolize xenobiotics, more specifically the enzyme CYP1A1 that is an isoenzyme of the CYP450 hepatic enzymatic system. In this work, chemometric methods were applied in the search for building discriminant models between active and inactive analogues, based on the correlations among their biological activities and electronic and geometric molecular descriptors. From 70 descriptors calculated with density functional theory (DFT) with the exchange correlation functional B3LYP and the basis set 6-31G* (Gaussian 03), 8 ones were pre-selected based on their Fisher weights, and finally five descriptors (A2, polarizability, and C20) were selected for a principal component analysis. This analysis was able to discriminate the analogues in active and inactive by using only one principal component, accounting for 77,9 % of the total variance. The cluster hierarchical analysis, using the descriptors selected by principal component analysis, shows that the piperine analogues can be grouped into two major groups: active and inactive. The results of this work can be used to help modeling new piperine analogues with more pronounced activity inhibition to the isoform CYP1A1.