Structural Analysis of SARS-CoV-2 Protease Inhibitors

The X-ray crystal structures of Mpro (7BQY) and PLpro (6WX4) in complex with potent covalent peptidomimetic inhibitors were downloaded from the Protein Data Bank. Both proteins were prepared using the Protein Preparation Wizard in Maestro (Schrödinger Release 2019-3, https://www.Schrodinger.Com), waters, and other co-crystallized molecules were removed, except for the ligand. Predicting protonation states of protein residues were calculated, considering a temperature of 300 °K and a pH of 7. The ligands were prepared using the Ligprep tool considering the ionization states at pH 7 ± 2. A 15 Å docking grid (inner-box 10 Å and outer-box 20 Å) was prepared using as centroid the co-crystallized ligand. The docking studies were performed using Glide SP precision, keeping the default parameters and setting, and it was combined with “molecular mechanics generalized Born surface area” (MMGBSA), implemented in the Prime module from Maestro to re-score the three-output docking poses of each compound. In the case of compound MG-101, a further analysis was performed using Covalent docking simulations implemented in Maestro (Covalent Dock Lead Optimization workflow) and the best poses were rescored with MMGBSA. Molecular Operating Environment 2019.1 (MOE) was used to visualize the structures and acquire the images.