Computational Methods DFT Calculations. Three structural models were constructed for density functional theory (DFT) calculations using the ligands 1-3 and the atoms from the amino acids in the first shell of the binding pocket; defined as all atoms of the receptor located within 8 Å of any atom of the respective ligand. Each model had a total number of atoms in excess of 500. All hydrogen atoms of the models were optimized at the DFT M062X/6-31G(d) level of theory with all positions of non-hydrogen elements fixed. After geometrical optimizations, BSSE (basis set superposition error) corrected calculations were carried out to obtain the interaction energy between the ligand and the receptor. The BSSE-corrected calculations were performed at two theoretical levels, one with at the M06-2X/6-31G(d) level of theory and the other with M06-2X functional and 6-311+G(d) basis set for O, N, Cl, and S elements and 6-311G(d) basis set for C and H elements. All calculations were performed with the Gaussian package, version C01. MD Simulations. The initial complex structures were prepared from the X-ray coordinates (PDB: 7RKE, 7RNM and 7SFO Chain B) using Protein Preparation Wizard within Maestro. The structural water molecules located within 8 Å from the binding site residues E353, R394, and the ligand in each structure were included. The initial systems for MD simulations were set up using antechamber and tleap programs in the AmberTools. The prepared structures were solvated in a rectangular box with a minimum 12 Å distance between the complex and box edges, and sodium ions were added to neutralize the system charges. MD simulations were performed with pmemd.cuda in Amber20 using Amber forcefields (ff14SB, tip3p and gaff2). All systems were equilibrated in NVT ensembles where they were heated to 310 K over 100 ps with 10.0 kcal/mol. The Å -2 harmonic restraints on the heavy atoms of the protein, ligand, and structural water molecules were retained from the initial PDB structure. Then, the restraints were gradually relieved over 1 ns in NPT ensembles. Three replicate simulations of 1 μs each were carried out for each protein-ligand complex. These simulations were performed using 2.0 fs timestep under constant pressure (1 bar) regulated by Monte Carlo barostat and constant temperature (310 K) regulated by Langevin thermostat with 2.0 ps -1 collision frequency.