Design computacional de inibidores de protoporfirinogênio ix oxidase como potenciais herbicidas

Abstract

Protoporphyrinogen IX oxidase (PPO) inhibitor herbicides are an effective class with a broad spectrum of applications. A combined computational approach including quantitative structure-activity relationships (QSAR), docking studies and molecular dynamics was developed to study the protoporphyrinogen IX oxidase inhibitory activities of a series of compounds containing diaryl ether-derived moieties, fluorinated benzoxazinones, phthalimides and benzothiazoles. In this context, new compounds belonging to these four classes of PPO inhibitors were recently synthesized with the purpose of modifying the chemical structures of similar and already known substances, thereby improving their herbicidal properties. The present work proposes the study of these compounds at the molecular level, with the objective of finding the chemophoric sites (i.e., portions of the molecular structure) responsible for the herbicidal activity of the four classes of molecules to be studied. For this, the computational molecular modeling methodology MIA-QSAR (Multivariate Image Analysis applied to Quantitative Structure-Activity Relationships) was used, as well as the MIA-Plot tool, whose design was guided by MIA graphs of varying importance in the projection scores (VIP) (Variable Importance in Projection) and PLS regression coefficients (b) (PLS regression coefficients) for the identification of chemophoric sites. Finally, the docking studies were able to validate the MIA-QSAR predictions and provided more information about the ligand-enzyme interactions that govern the bioactivities of these compounds. MIA plots, as well as docking and molecular dynamics studies are crucial for understanding how different substituents are related to biological activity. Therefore, hitherto unknown compounds were proposed based on these characteristics and proved to be stable at the PPO binding site. Consequently, a synthetic route to obtain these promising herbicides has been proposed.