Ligand Docking in ICM-Pro: Fundamental Workflow
This tutorial follows the EGFR Kinase (PDB: 1M17) redocking example. This workflow is essential for validating docking parameters and performing lead optimization.
1. Protein Structure Preparation
Before docking, raw PDB files must be converted into flexible ICM objects to resolve chemical ambiguities.
- Load Receptor: Search for PDB code
1m17 [00:09:12].
- Convert to ICM Object: Right-click the object and select Convert PDB [00:11:18].
- Delete Loose Waters: Removes non-bridging water molecules [00:11:34].
- Optimization: Corrects hydrogen-bonding networks and sets proper protonation states [00:12:01].
2. Identifying the Binding Pocket
Use ICM Pocket Finder to map potential binding sites and allosteric cavities.
- Run Pocket Finder: Navigate to
Tools > 3D Predict > ICM Pocket Finder [00:12:53].
- Analyze Results: Pockets are ranked by "Drugability" (Merck - DLID score developed in ICM). The ATP-binding site is typically the top-ranked pocket for 1M17 [00:14:13].
3. Redocking Setup
Extract the native ligand to create an empty pocket for testing docking accuracy.
- Move Ligand from Pocket: Right-click the ligand (Erlotinib) and select Move from Object [00:17:36].
- Prepare Ligand Table: Use the Molecular Editor to load the ligand into a chemical table [00:18:44].
4. Initializing the Docking Project
The project defines the physics-based potential maps of the binding pocket.
- New Project: Go to
Docking > New Project and name it (e.g., dock_egfr) [00:20:24].
- Define Binding Site: Click Define Site around the pocket residues [00:21:55].
- Generate Grid Maps: Ensure the Purple Box encompasses the entire pocket and click Go to calculate potential maps [00:23:50].
5. Execution and Scoring
ICM uses Biased Probability Monte Carlo (BPMC) to search for the optimal pose.
- Run Docking: Select
Docking > Doc Chemical Table. Set Thoroughness (e.g., 1.0 or 3.0) [00:24:23].
- Scoring: Review the ICM Score (physics-based) and RT CNN Score (deep-learning). Lower values are better [00:29:12].
6. Analysis and Validation
- Visual Inspection: Click entries in the result table to overlay docked poses in 3D [00:32:11].
- RMSD Calculation: Use
Tools > Analysis > RMSD to compare the docked pose to the crystal ligand. Success is usually < 2.0 Å [00:33:47].
7. Advanced: Template-Based Docking
- Define Template: Designate a core scaffold (e.g., quinazoline ring) as a template [00:36:45].
- APF Similarity: Match the 3D pharmacophore using Atomic Property Fields to maintain critical interactions [00:39:08].
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