Study of Molecular Dynamics, NBO and QTAIM for inhibitors of ALK-5

Introduction: TGF-β Receptor Type 1 (TGF-β1), also known as activin kinase type 5 (ALK-5), is a biological target related to some types of cancer, such as breast cancer. Inhibition of this target is a strategy that has been studied as a way to treat cancer. In this way, the objective of this work is to use computational chemistry to evaluate the main interactions that occur between the main residues in the active site of ALK-5 (Tyr249, His283 and one structural water) and two inhibitors of this receptor [1, 2]. Materials and methods: To evaluate the interactions between the two molecules and the ALK-5 target, the following methodologies were used: molecular docking (GOLD 5.2), molecular dynamics (70 ns, force field ff99SB, AMBER12), QM/MM (ONIOM, B3LYP/cc-PVDZ:UFF, Gaussian 09), analysis of natural bond orbitals (NBO, B3LYP/cc-PVDZ, Gaussian 09) and topological analysis of electronic density of interactions by quantum theory atom in molecules (QTAIM) [3]. Results and discussion: Figure 1 shows the results obtained from molecular docking and molecular dynamics simulations.