The ligand, water, and the ions were first minimized for 1000 steps keeping the protein fixed using 25 kcal/mol-Å 2 positional restraints and then for another 1000 minimization steps with 10 kcal/mol-Å 2 restraints. The system was next heated from 10 K to 300 K in NVT ensemble for 140 ps while restraining the protein-ligand complex using positional restraints of 10 kcal/mol-Å 2 . Next, the restraints were gradually released using 5 and 2 kcal/mol-Å 2 restraints on the protein-ligand complex for 20 ps each, and then 2 kcal/mol-Å 2 restraint only on the ligand for 20 ps. The temperature was regulated in the NVT simulations through Langevin dynamics with a collision frequency of 2 ps -1 . The production run was performed in NPT ensemble for 14 ns with the first 4 ns being discarded as equilibration. Constant pressure was maintained in the simulation using isotropic pressure scaling with a relaxation time of 2 ps. After generating trajectories using MD simulations, we used the MMPBSA.py program in Amber16 to calculate the protein-ligand binding scores using the GBneck2 model with a salt concentration of 0.1 nM. Coordinates were saved every 100 ps during MD, resulting in 100 frames which were analyzed for the MM-GBSA calculations for each ligand.