Initially, the energy was minimized using the steepest descent method for 5,000 steps, followed by another 5,000 steps with the conjugate gradient method to remove any bad contacts. The system was then gradually heated from 0 K to 300 K in increments of 50 K over a period of 25 ps while maintaining the canonical ensemble (NVT) conditions. During these steps, all heavy atoms of the protein-ligand complexes were fixed with a harmonic restraint of force constant 5 kcal mol -1 Å-2 to their energy-minimized configurations. Subsequently, sim-ilar sequences of equilibration (NVT) were performed with progressively reduced positional restraint forces of 2, 1, 0.5, 0.1, and eventually 0 kcal mol -1 Å-2 . A 1 ns NPT equilibration was performed to maintain the density, followed by a 100 ns NVE simulation.