MD/NCMC implemented using BLUES software package. We implemented our MD/NCMC protocol using BLUES version 0.1.3. The MD simulations were performed using OpenMM, while the NCMC part used openmmtools 0.14.0 37 for turning the ligands on and off alchemically. Only the flexible region of the ligand (Figure ) was selected as the alchemical region. During the NCMC move, all atoms more than 5 Å away from the ligand were frozen to increase move acceptance rates. OpenEye Toolkits 3.0.8 (OpenEye Scientific Software) was used to set the selected torsion angles (shown in Figure ) to random values during NCMC move proposal.