In silico inhibitor docking for human TMPRSS2
Description
TMPRSS2 is a human protein that SARS-CoV-2 uses for viral entry and is potential target for developing prophylaxis treatment. Using a unique structural phylogenetic approach, we identified several candidate compounds that have the capability to inhibit TMPRSS2. These compounds were evaluated with in silico docking calculations.
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Steps to reproduce
A model of the TMPRSS2 S1-peptidase domain was generated with the Hepsin template (41% sequence identity; PDB 1Z8G) using Phyre2. Published crystal structures of inhibitor-bound Trypsin-3 (PDB 1H4W), KLKB1 (PDB 6O1S), and Coagulation Factor VII (PDB 1W7X) and the TMPRSS2 model were loaded into Maestro software (Schrödinger Release 2019-3). The TMPRSS2 model described above was used. To prepare the proteins for docking and simulations, the protein preparation wizard was used to assign bond orders, add hydrogens, create zero-order bonds to metals, create disulfide bonds, and fill in missing side chains and loops. The default parameters were used for the optimization of hydrogen-bond assignment (sampling of water orientations and use of pH 7.0). Waters molecules beyond 3 Å of heteroatoms or with fewer than three hydrogen bonds to non-waters were removed. Restrained energy minimization was applied using the OPLS3e force field (Harder et al., 2016). Prepared protein systems were further checked by Ramachandran plots, ensuring there were no steric clashes. To generate receptor grids for small molecule docking, the co-crystalized ligand was selected as the grid-defining ligand for each system. Default van der Waals radius scaling parameters were used (scaling factor of 1, partial charge cutoff of 0.25). For peptides, the grid size was made suitable for peptides to be docked. Default van der Waals radius scaling parameters were used (scaling factor of 1, partial charge cutoff of 0.25). For docking of the ligands into the various prepared proteins, the 3D structure was loaded into Maestro software (Schrödinger Release 2019-3). Ligprep was used to prepare the ligands (by generating possible states at pH 7.0 ± 2.0 and retaining the specified stereochemical properties). The prepared small molecule ligands were then docked using the most stringent docking mode (extra precision, “XP”) of Glide, with the following parameters: dock flexibly, perform post-docking minimization, and show only top 2 posed for each ligand (Friesner et al., 2006). The prepared peptide segments were docked using the standard precision more for peptides in Glide, with the following parameters: dock flexibly, perform post-docking minimization, and show the top 100 posed for each ligand.