Abstract
Cancer is a very complex disorder, and it is urgent to find new ways to treat it. This study aims to evaluate the inhibition mechanism of ALK-5 (target related to breast cancer) from an electronic point of view. Computational simulations (QM/MM, NBO, QTAIM) were performed, and the ONIOM method (B3LYP/cc-pVDZ:UFF) was used to obtain the optimized geometries of the studied systems. The NBO analyses indicated that the most important electron transfer occurs between LP N (inhibitor 1) and BD* O–H (Tyr249) orbitals (ΔE2 = 11.89 kcal/mol). The weakest interaction occurs between the LP N (inhibitor 4) and BD* N–H (His283) orbitals (ΔE2 = 0.81 kcal/mol). The QTAIM analyses suggested that the most active inhibitors perform a greater number of hydrogen bonds with the major residues. Therefore, quantum mechanics methods proved to be important to better understand the inhibition of ALK-5, as well as helping the design of new inhibitors.
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