In Silico Discovery of Fructosamine-3-Kinase Inhibitors Targeting the Nrf2-Mediated Antioxidant Response in Cancer Cells: A Molecular Dynamics Approach

Fructosamine-3-kinase is an enzyme responsible for deglycating the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) which regulates the expression of numerous genes involved in the cellular defence against oxidative stress. To identify inhibitors against FN3K, which may disrupt antioxidant-homeostasis in cancer cells, noncovalent docking was performed for a set of 83 ATP-mimicking kinase inhibitors, followed by flexible side-chain docking to re-confirm the trend in binding energies. Covalent docking was also performed for a set of 36 known covalent kinase inhibitors with the active site Cys150 residue. The recently reported crystal structure of Human FN3K [PDB:8UE1] was employed for docking. The pharmacokinetic and toxicological properties of the top noncovalent and covalent inhibitors were subsequently studied. Kinase inhibitors with appropriate ADMET properties that are suitable for human administration and have favourable binding energies were subjected to molecular dynamics simulations to study the stability of their protein-ligand complexes. On the basis of 110 ns MD simulations, it was concluded that trilaciclib, tucatinib and olmutinib can be considered candidate inhibitors for HsFN3K inhibition. Trilaciclib and tucatinib also showed favourable thermodynamic binding free energies of -23.37 ± 3.03 and − 18.36 ± 1.83 kcal/mol respectively, as calculated via MM/PBSA method. Olmutinib displayed very stable binding as a complex with FN3K with no dramatic shifts in protein structure or having any impact on its folding. The solvation and hydration effects seen on the ATP-binding site in response to ligand-binding were also extensively studied which corresponds to efficient ligand entry. These drugs are expected to have favourable in-vitro and in-vivo activity inhibiting HsFN3K on the basis of our results.