This section allows users to perform covalent molecule design for targets of interest. The process includes identifying amino acid residues near the target's binding pocket that are capable of forming covalent bonds, and then selecting the desired target residue. Subsequently, new covalent molecules were generated based on either the existing covalent warheads provided by the system or by uploading custom warheads.

1.1 In the “Pocket Select” module, users can choose a target protein-ligand complex using one of the following two methods:
A. Enter a PDB ID directly (e.g., PDB ID: 3EQR)
B. Upload a local structure file (standard PDB format supported)
The system will automatically load the structure and identify the ligand. After confirming the ligand information, click the "Continue" button to proceed to the next step.

In the following settings, users can define a distance threshold between the ligand and nearby amino acid residues. This is used to identify potentially covalently targetable amino acids near the ligand binding site. A recommended range is 3 to 7 Å, with a default value of 6 Å.

1.2 In the “Residue Select” module, users can select target covalent amino acid residues through the following methods:
A.Click on the covalently targetable residues displayed on the left panel to directly choose the residue of interest;
B. Alternatively, users can manually enter or select the amino acid type from the dropdown menu in the "Select residue type" area, and then specify the exact residue position. These options allow users to accurately define the desired covalent amino acid target, facilitating downstream design.

1.3 In the "Warhead Select" module, the system offers three methods for warhead selection:
A. Select System-Provided Covalent Modification Warheads
• Click the "CM" button
• Set the fragment retention score (recommended: 0.2-0.3, default: 0.2)
• Choose one or multiple target warheads through the dropdown menu, or use the SVG choose feature for visual selection
• Click the "Run" button to generate the designed covalent molecule

B. Select Post-Translational Modification Warheads
• Click the "PTM" button
• Set the fragment retention score (recommended: 0.2-0.3, default: 0.2)
• Choose one or multiple target warheads through the dropdown menu, or use the SVG choose feature for visual selection
• Click the "Run" button to generate the designed covalent molecule

C. Custom Warhead Design
• Click the "CUSTOM" button
• Set the fragment retention score (recommended: 0.2-0.3, default: 0.2)
• Click the "CUSTOM MOL" button to open the structure drawing interface
• Complete the warhead structure design and submit
• Click the "Run" button to generate the designed covalent molecule

After completing warhead selection through any of these methods, the system will display the newly designed covalent molecule structure on the results page. Taking the covalent molecules generated from system-provided warheads as an example, the results page displays three columns of key information:
A. Generation Position of Covalent Warhead: Indicates the specific attachment position of the newly introduced covalent warhead in the parent compound;
B. Generated Covalent Molecule Structure: Shows the complete structure of the newly designed covalent molecule by the system;
C. Related Covalent Binding Mechanism: Provides information about the covalent reaction mechanisms of the warhead, helping users understand its reaction type and targeting approach.

For users who have identified a warhead capable of reacting covalently with a specific amino acid, this section analyzes binding pockets to identify the presence of target amino acids and recommends potential targets accordingly. Users can then select their targets of interest, combined with their custom warhead structures, utilize the platform to generate corresponding covalent molecules.

2.1 In the " Warhead Input" module, click the "Edit Warhead Structure" button to draw the known covalent warhead structure (e.g., salicylaldehyde), and submit it once completed. Then, click the "Advanced Search" button.

In the Residue Selection module, users can select amino acid types to be included or excluded based on the reactivity of their custom warhead (for example, searching for complexes that include Lys residues). Additionally, users can set the distance range between amino acid and the nearest atom of the ligand within a protein-ligand complex according to the spatial requirements of the warhead (e.g., 3.5–4.0 Å) to further refine the search results.
The system will return protein-ligand complexes that meet the criteria, categorized into six major target classes for user selection (e.g., selecting the complex with PDB ID: 1g5s from the “Enzyme” category).

After selecting a specific protein-ligand complex, the system will display the ligands it contains. Users can then confirm the target ligand. Once confirmed, click the “Continue” button to proceed to the next step.

2.2 In the "Residue Select" module, users can determine their target covalent amino acid residue through the following methods: users can either click on the covalent amino acid displayed on the left side of the interface, or use the "Residue Select" area to input or choose amino acid types and specify exact positions to determine the covalent amino acid for modification.
Next, enter the Fragment Retention Score, with a recommended range of 0.2-0.3 and a default value of 0.2.
After clicking the "Run" button, the system will generate and display new covalent molecular structures featuring the custom warhead designs.