Ligand Docking with Glide

Proteins and ligands were prepared using Schrödinger’s Maestro (version 11.4, 2017-4 release) Prep Wiz and LigPrep modules, respectively, with default settings for docking with Glide. All covalent docking simulations were performed using the CovDock module available in Glide.⁹² For the noncovalent simulations, the grid was generated using XGlide, which enables creation of different grids in parallel. The grids were centered around the ligand’s centroid. The dimensions of the enclosing box and the bounding box were set to 12 × 12 × 12 ų and 26 × 26 × 26 ų, respectively, for all cases. The ligand stereochemistry was kept during all docking simulations. The number of poses written per ligand was set to 10,000. The scaling factors of the vdW radii and the partial atomic charge cutoff were set to the default values 0.80 and 0.15, respectively. Standard precision (SP) mode was chosen for all ligand docking runs. The selection of the best-docked ligand structure among the proposed poses is made based on several model energies implemented with Glide (docking score, Prime energy and E-model energy, and cdock affinity). Solvent effects were incorporated using MMGBSA. All reported energies herein used the docking score function for noncovalent docking and the cdock affinity scoring function for covalent docking as these performed best [i.e., produced the highest number of top-ranking structures with root-mean-square deviation (rmsd) < 2 Å]. In all Glide docking simulations (ligand preparation, protein preparation, grid generation, covalent, and noncovalent docking), the OPLS3 force field^59,93 was used.