Molecular dynamic simulations give insight into the mechanism of binding between 2-aminothiazole inhibitors and CDK5

Molecular docking, molecular dynamics (MD) simulations, and binding free energy analysis were performed to reveal differences in the binding affinities between five 2-aminothiazole inhibitors and CDK5. The hydrogen bonding and hydrophobic interactions between inhibitors and adjacent residues are analyzed and discussed. The rank of calculated binding free energies using the MM-PBSA method is consistent with experimental result. The results illustrate that hydrogen bonds with Cys83 favor inhibitor binding. The van der Waals interactions, especially the important contact with Ile10, dominate in the binding free energy and play a crucial role in distinguishing the different bioactivity of the five inhibitors.