Modelos de QSAR-4D e ancoramento molecular aplicados ao estudo de inibidores da proteína TGF-β1 para o tratamento do câncer

Abstract

Cancer is a disease that affects millions of people around the world, it is characterized by abnormal cell growth, which manifests itself aggressively and uncontrollably. There are several types of treatment for cancer, however they are most effective in the early stages, so it is essential to discover new treatments for cancer in advanced stages. In this perspective, the members of the TGF-β subfamily are considered interesting molecular targets, since they play important function in growth and development cell. Therefore, the objective of this work was to quantitatively determine the influence of structural descriptors on the activity of aryl pyrimidine derivatives as inhibitors of the TGF-β1 protein, from the application of QSAR-4D studies and to analyze the mode of interaction between these inhibitors and TGF-β1 protein through the molecular docking. This study was carried out in order to understand the affinity of the inhibitors with the protein and to identify which factors are relevant for the inhibition of the signaling pathway. The 4D-QSAR models presented good statistical parameters (R2 = 0.792, Q2 = 0.584, R2pred = 0.648, r2m = 0.547, R2P = 0.681 and R2rand = 0.207) besides pharmacophores groups important for the activity of these compounds. From the docking, the interactions between protein and ligand were analyzed, in which it was verified that amino acid residues like His283, Asp351 and Lys232 perform hydrogen bonding with most of the compounds. In contrast, Leu340, Ile211 and Val219 residues perform important steric interactions with groups that were considered favorable in QSAR. From these results, ten new structures were proposed, which had their activity predicted from the model obtained by QSAR-4D. All presented good interaction energies calculated by molecular docking and four presented predicted activities superior to those of the compounds studied. Therefore, the results suggest that these four compounds can be considered as potent prototypes of inhibitors of the TGF-β1 protein for the treatment of cancer.