All simulations were carried out with Gromacs 2018 . The ligand topologies were generated using the ACPYPE/ANTECHAM-BER program of AmberTools17 with partial charges generated by the empirical charge model AM1-BCC. The ligands parameters are based on the General Amber Force Field (GAFF) and the Amber FF14SB force field was employed for the proteins. Each complex was solvated in a TIP3P water dodecahedral box, with periodic boundary conditions and a minimum distance of 1.0 nm from the surface of the complex to the edge of the box. Each system was neutralized by adding NA+ and Cl-ions to physiological concentration of 153.6 mM. A completely free steepest descent energy minimization for 2000 steps was followed by a 100-ps NVT equilibration and a 100-ps NpT equilibration with Parrinello-Rahman pressure coupling. NVT and NpT equilibrations were performed at a reference temperature of 300 K with ligand restraints of 1000 kJ/mol nm 2 in x,y,z directions. Finally, 50 ns unrestrained production runs were performed with a 2 fs time-step in the NpT ensemble and snapshots were saved every 10 ps. For each of the four ligands (DB, CDB, HDB, and DDB) five replica simulations were run with different randomly assigned initial velocities, resulting in a total of 250 ns simulation per ligand.