We apply molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation to investigate and reveal the binding mechanism between five xanthine inhibitors and DPP-4. The electrostatic and van der Waals interactions of the five inhibitors with DPP-4 are analyzed and discussed. The computed binding free energies using MM-PBSA method are in qualitatively agreement with experimental inhibitory potency of five inhibitors. The hydrogen bonds of inhibitors with Ser630 and Asp663 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the key contacts with His740, Asn710, Trp629, and Tyr666 have larger contributions to the binding free energy and play important roles in distinguishing the variant bioactivity of five inhibitors.

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.