If you’re working with covalent inhibitors, you probably know that setting up covalent docking studies can be tricky. From ensuring the correct chemical structure of your ligand to modifying protein residues involved in the covalent interaction, every detail impacts your final results.
In this post, we’ll walk through a practical, fully-integrated way to perform covalent docking using the FITTED Suite in SAMSON. You’ll see how to set up a receptor-ligand system with a covalent bond, ensure correct bond orders and hybridization, and run docking—all using a simple graphical interface.
Why Covalent Docking?
Covalent inhibitors form irreversible bonds with target proteins, offering advantages like prolonged target engagement and strong potency. But preparing systems for docking covalent ligands can be error-prone and time-consuming.
The FITTED Suite, developed in partnership between SAMSON and Molecular Forecaster, helps streamline this process by integrating structure editing, ligand preparation, and docking workflows in a single interface.
Twist: Your Ligand Might Need a Bit of Chemistry First
Let’s look at a practical example: docking a nitrile ligand (7KH 301) into a human cathepsin L enzyme (5MAJ). Before setting up the docking job, pay attention to a few key details:
- Bond order correction: The nitrile group (C≡N) in the ligand might appear as a single bond in the structure. You’ll need to change the
C8–N7bond to a triple bond. - Atom hybridization: Set the hybridization of
C8andN7toSPto reflect the correct geometry.
This can be done directly in SAMSON using either the Edit > Edit bonds tool or the Inspector.
Setting Up the Docking
The FITTED Suite workflow involves three steps:
- Select the receptor (e.g., protein 5MAJ)
- Define the binding site from the covalently bound ligand
- Select the ligand and disable automatic preparation if bond order was modified manually
Next, choose the docking mode as Covalent only and set the number of runs and file output directory. Then, define:
- Covalent residue: Typically, the one containing the nucleophilic atom (e.g.,
CYS 25) - Basic atom (optional): An adjacent residue such as
HIS 163 ND1
Click Dock and wait a few minutes for the calculation to finish. The FITTED Suite will identify possible poses and return results in a sortable table.
Inspecting the Results
Once complete, the post-docking structure will show the processed receptor (e.g., 5MAJ_pro) and the ligand covalently bound to it. You can now visualize interactions, hide the original structure, and generate visuals for publication or further analysis.
Final Thoughts
Preparing a covalent docking system might sound like a niche task—until you actually have to do it. The FITTED Suite in SAMSON makes it much more accessible. From proper structure editing to visualization and result interpretation, the workflow reduces friction in a task that molecular modelers often struggle with.
To explore this process in more depth, visit the full SAMSON FITTED Suite tutorial.
SAMSON and all SAMSON Extensions are free for non-commercial use. You can get SAMSON at https://www.samson-connect.net.