Modelagem MIA-QSAR e docking molecular na proposição de novas tricetonas como potenciais inibidoras da enzima

Abstract

The problem of weed resistance has caused significant concern and has guided studies regarding herbicidal compounds. To propose new candidates to overcome this recurring problem in the class of triketones, two sets of molecules were subjected to MIA-QSAR modeling. The descriptors initially obtained in pixel values of the RGB scale were translated to consider the effects of electronegativity (ε), van der Waals radius (rvdW) and the rvdW/ε ratio, and subsequently submitted to the PLS regression method, with validation carried out from a sample randomization procedure. The results obtained in both sets demonstrate that the three evaluated parameters contributed significantly to the observed activity of the compounds, with the set of activities at pIC50 showing better values for the parameter rvdW/ε, whose average for 15 cycles was R2 = 0.823 ± 0.022, Q2 = 0.685 ± 0.027, R2pred = 0.702 ± 0.099, all acceptable values being above 0.5. In the set of activities related to pKi, only one model proved to be predictive, generating statistical values of R2 = 0.7180, Q2 = 0.5090, R2pred = 0.7101. The MIA plot's b and VIP were used to evaluate the influence of substituents on the response variables and, subsequently, to propose new candidates; 8 and 14 structures with better activity than the standard commercial compound mesotrione were obtained for the sets containing in vitro activities in pIC50 and pKi respectively. Molecular docking analyzes were carried out in a complementary way, aiming at investigating the interactions of the proposed molecules with the active site of the enzyme hydroxyphenylpyruvate dioxygenase (HPPD), indicating that, for both sets, the proposals with better activity presented greater stability in the enzymatic complex of the than the highest activity structure of the total pool and the standard compound mesotrione. The chemical synthesis of compounds becomes, therefore, promising in validating the theoretical evidence presented in this work.