Binding free energy analysis. A) g_mmpbsa calculated the binding free energies of REF1, REF2, Hit1, and Hit2 with Cdk5/p25 throughout the simulation time. Hit1 and Hit2 showed slightly low binding free energies than REF1 and REF2. The binding free energy of Cdk5/p25 with REF1, REF2, Hit1, and Hit2 has been depicted as green, blue, magenta, and orange, respectively. B) Energy decomposition analysis showed that Van der Waals (VdW) and polar solvation energies (PSE) played differential roles in the binding free energies of Hit1 and Hit2. Coloring scheme: REF1, Green; REF2, Blue, Hit1, Magenta; and Hit2, Orange. Energy decomposition factors: VdW, Van der Waals; Elec, Electrostatic energy; PSE, Polar solvation energy; SASA, Solvent accessible surface area energy; BFE, Binding free energy. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)