Abstract

Background: The quantitative structure-activity relationship is an analysis method that can be applied for designing new molecules. In 1997, Hopfinger and coworkers developed the 4DQSAR methodology aiming to eliminate the question of which conformation to use in a QSAR study. In this work, the 4D-QSAR methodology was used to quantitatively determine the influence of structural descriptors on the activity of aryl pyrimidine derivatives as inhibitors of the TGF-β1 receptor. The members of the TGF-β subfamily are interesting molecular targets, since they play an important function in the growth and development of cell cellular including proliferation, apoptosis, differentiation, Epithelial-Mesenchymal Transition (EMT), and migration. In late stages, TGF-β exerts tumor-promoting effects, increasing tumor invasiveness, and metastasis. Therefore, TGF-β is an attractive target for cancer therapy.

Objective: The major goal of the current research is to develop 4D-QSAR models aiming to propose new structures of aryl pyrimidine derivatives.

Materials and Methods: Molecular dynamics simulation was carried out to generate the conformational ensemble profile of a data set with aryl pyrimidine derivatives. The conformations were overlaid into a three-dimensional cubic box, according to the three-ordered atom alignment. The occupation of the grid cells by the interaction of pharmacophore elements provides the Grid Cell Occupancy Descriptors (GCOD), the dependent variables used to build the 4D-QSAR models. The best models were validated (internal and external validation) using several statistical parameters. Docking molecular studies were performed to better understand the binding mode of pyrimidine derivatives inside the TGF-β active site.

Results: The 4D-QSAR model presented seven descriptors and acceptable statistical parameters (R² = 0.89, q² = 0.68, R² _pred = 0.65, r² _m = 0.55, R² _P = 0.68 and R² _rand = 0.21) besides pharmacophores groups important for the activity of these compounds. The molecular docking studies helped to understand the pharmacophoric groups and proposed substituents that increase the potency of aryl pyrimidine derivatives.

Conclusion: The best QSAR model showed adequate statistical parameters that ensure their fitness, robustness, and predictivity. Structural modifications were assessed, and five new structures were proposed as candidates for a drug for cancer treatment.

Keywords: Molecular modeling, 4D-QSAR, molecular docking, TGF-β receptor, Aryl pyrimidine, Cancer.

Graphical Abstract