For molecular modelers and drug designers, covalent docking is often seen as a complex and time-consuming task. It typically requires careful preparation of ligands and receptors, as well as software tools that can accurately model the formation of covalent bonds between drug candidates and their targets.
Fortunately, the FITTED Suite in SAMSON provides an accessible and streamlined approach to covalent docking. Powered by Molecular Forecaster’s docking engine, it allows users to perform even sophisticated docking tasks directly through an intuitive graphical interface.
This post walks you through a key use case featured in the documentation: performing covalent self-docking using the 5MAJ protein-ligand complex. The ligand is covalently bonded to the protein receptor (human cathepsin L), making it an excellent example to learn from.
Start by Opening Your System
First, download and open the 5MAJ.sam file provided in the FITTED tutorial archive. You can drag and drop the file into SAMSON or use Home > Open in the main menu.
Optional: Bond Order and Hybridization Adjustments
If your ligand is already covalently bound in the structure (as with 5MAJ), you might need to manually adjust bond orders and hybridizations. In this case, the bond between atoms C8 and N7 in the ligand is converted to a triple bond, and both atoms are marked with SP hybridization.
Setting Up the Docking
Launch the FITTED Suite app via Home > Apps > Biology. You’ll need to define:
- Receptor: Select the 5MAJ model and click Set.
- Binding site: Select the bound ligand (7KH 301) and choose From bound ligand.
- Ligand: Select the 7KH 301 ligand, uncheck Prepare ligand so that custom parameters are preserved.
Defining Covalent Docking Parameters
FITTED supports covalent docking with parameters tailored for reactivity. For 5MAJ, the sulfur atom in the CYS 25 residue is the reactive site. Optionally, set a basic atom such as ND1 in HIS 163 to simulate proton shifts.
In the docking options, set the mode to Covalent only, limit the number of runs (e.g., 2), and specify an output folder.
Running and Analyzing Results
Once you click Dock, SAMSON will begin the docking process. When complete, the results appear in a table and are automatically loaded into your document.
Structure (5MAJ_pro) with hydrogen atoms and the docked pose will be visible. You can further analyze or visualize the results using the ribbon model or by zooming into the binding interface.
Conclusion
Using the FITTED Suite in SAMSON, setting up and performing covalent protein-ligand docking is straightforward, even when accounting for bond orders, hybridizations, and advanced docking parameters. This makes it easier to evaluate reactive inhibitors and their interactions with macromolecular targets.
To explore more use cases and tools for protein-ligand docking, visit the full FITTED Suite SAMSON Extension documentation.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can download SAMSON at https://www.samson-connect.net.