MD simulations were performed using Amber (). The force field parameters for small molecules were adapted from the Amber GAFF force field, with point charges of atoms calculated via AM1-BCC. The protein was described by the Amber FF19SB force field and solvated in an OPC water box with a 12-Å buffer. KCl ions were added into the system to neutralize the charge. The system was first energy-minimized using the steepest descent algorithm for 200 steps followed by the conjugate gradient algorithm for 9800 steps. The system was then heated from 0 to 100 K in the NVT ensemble over 800 ps and from 100 to 300 K in the NPT ensemble over 2 ns. During the heating stage, the backbone of the protein was restrained by a harmonic constraint with a force constant of 5 kcal/mol/Å 2 . A 1-ns equilibrium simulation with force constant reduced to 1 kcal/mol/Å 2 was then performed to relax the system. The equilibrated system was used to initiate a 200-ns production run. During the simulations, the SHAKE algorithm 48 was used to restrain the lengths of bonds that involve hydrogen. The hydrogen mass repartition operation, which redistributes the masses of heavy atoms to their bonded hydrogens, was performed to enable a 4-fs time step for MD simulations. The Langevin thermostat was used during the simulations, and the equilibration and production runs were performed in the NPT ensemble at 300 K. The non-bonded interaction cutoff was 10 Å. For each of the selected binding poses, its 200-ns MD trajectory with the protein was subjected to MM-GBSA 49 to estimate the binding free energy. The ionic strength was set at 0.15 M. The binding poses were re-ranked according to their MM-GBSA binding free energies. Finally, we identified and selected the three top-ranked poses and extended their simulations to 1 μs.