When preparing a molecular docking project, many researchers focus on the setup of the receptor, defining the search space, or choosing the scoring function. One critical but sometimes overlooked step is the minimization of ligands before docking. Neglecting this can have a significant impact on the quality of your results, especially if your ligands are imported in 2D or suffer from distorted geometries.
Let’s look at why ligand minimization matters, when you need it, and how you can easily perform it as part of your workflow using the AutoDock Vina Extended App in SAMSON.
Why ligand minimization matters
Docking algorithms such as AutoDock Vina assume that the starting conformation of the ligand is physically reasonable. If the input ligand has strain, incorrect bond lengths or angles, or lacks 3D structure altogether, the algorithm may spend computational effort fixing geometry issues rather than exploring relevant binding modes. This can lead to:
- Reduced docking accuracy
- Higher docking times
- Increased chances of generating invalid poses
Minimization helps by ensuring that your ligand starts from a realistic and low-energy structure. This is doubly important when docking libraries of ligands, where molecules might come in various states of completeness.
When should you minimize ligands?
- If your ligands are in 2D format.
- If they lack hydrogens.
- If they come from public databases but don’t appear geometry-optimized.
- If you generated them manually or edited them in a molecular editor.
In AutoDock Vina Extended, you can choose to minimize individual ligands or an entire ligand library using built-in options.
How to perform ligand minimization in SAMSON
Once you’re inside the AutoDock Vina Extended app and have selected your ligand or ligand library, simply check the Minimize box before running the docking session:
You can also specify:
- Minimization preset: Choose presets that control the number of steps and stopping conditions.
- Add missing hydrogens: Ensures hydrogen bonds can be detected during docking.
Some tips:
- Minimization does not respect locked (non-rotatable) bonds—those constraints apply only during docking.
- Cis-trans isomerization is not handled during minimization. Make sure all relevant isomers are included if needed.
Results you can trust
By starting with minimized and chemically valid ligands, you increase the likelihood of meaningful docking poses and ranking. You avoid wasting computation on correcting input geometries and ensure that the docking score reflects binding affinity rather than structural repair.
Whether you’re running a single ligand or screening a library from ZINC, adding this step can help surface promising compounds that could otherwise be missed due to bad input conformation.
To learn more about how to prepare your system and ligands for docking in SAMSON, check the full AutoDock Vina Extended tutorial here.
SAMSON and all SAMSON Extensions are free for non-commercial use. Get it at https://www.samson-connect.net.