> ## Documentation Index
> Fetch the complete documentation index at: https://docs.boltz.bio/llms.txt
> Use this file to discover all available pages before exploring further.

# Example Bond: Covalent Inhibitors

> Guide to modeling covalent inhibitors using the Bond constraint in Sandbox mode

***

## Introduction

This guide will use the covalent inhibitor AMG 510 bound to KRAS G12C (PDB Code 6OIM) as an example prediction.

<Danger>
  Modeling of covalent inhibitors is enabled within Boltz Lab, and currently limited to the Sandbox mode.
</Danger>

<Tip>
  To specify a covalent bond, use the \*\*Bond \*\*constraint option on the \*\*Constraints \*\*page. This allows you to define which atoms should form a covalent connection between your ligand and protein residue.
</Tip>

***

## Submitting a Prediction

### Step 1: Create New Prediction

In Sandbox, click **New Prediction** to get started.

After naming your prediction with an identifiable description, add:

* Target protein
* Post-modified small molecule
* Any cofactors to be included in the complex

<Tip>
  In this example, to model the bound acrylamide warhead, add the SMILES string for AMG 510 containing an ethyl-substituted amide.
</Tip>

<Frame>
  <img src="https://mintcdn.com/boltzpbc/vVhblbMfOGhVgP3r/images/user-guide/covalent-setup.png?fit=max&auto=format&n=vVhblbMfOGhVgP3r&q=85&s=89c324574243aa4902887628f5238d5d" alt="Setting up a covalent inhibitor prediction" width="993" height="457" data-path="images/user-guide/covalent-setup.png" />
</Frame>

### Step 2: Configure Bond Constraint

On the **Constraints** page, select **Bond** to guide the prediction. The Bond constraint is used to specify a covalent bond between different atoms in the complex.

1. **Select the Protein residue** that you wish the model to covalently modify
2. **Select the Ligand** from the left-hand side

For PDB ID 6OIM, choose:

* **Ligand**: MOV
* **Residue number**: 26

<Frame>
  <img src="https://mintcdn.com/boltzpbc/vVhblbMfOGhVgP3r/images/user-guide/covalent-constraints.png?fit=max&auto=format&n=vVhblbMfOGhVgP3r&q=85&s=86c46df6235e583b3aeb03f29e511d52" alt="Configuring bond constraints for covalent inhibitor" width="715" height="518" data-path="images/user-guide/covalent-constraints.png" />
</Frame>

### Step 3: Define Atom Connections

Using the right-hand side drop-down menus and atom labeling schematic, select the atoms to be connected.

In this example:

* **Ligand atom**: C25
* **Protein residue atom**: SG

Click **Add Bond Constraint**, and continue through the remaining steps.

***

## Viewing Results

When inspecting the predicted structure, the covalent bond between ligand and protein is now present.

<Frame>
  <img src="https://mintcdn.com/boltzpbc/vVhblbMfOGhVgP3r/images/user-guide/covalent-results.png?fit=max&auto=format&n=vVhblbMfOGhVgP3r&q=85&s=7cd290bbe4660180f0ac8dc808d0eb88" alt="Results view showing covalent bond formation" width="864" height="677" data-path="images/user-guide/covalent-results.png" />
</Frame>

<Info>
  The prediction results will show the covalent bond formed between the selected atoms, along with standard Boltz prediction metrics including binding likelihood, predicted affinity, and structure confidence scores.
</Info>

***

## Key Considerations

<AccordionGroup>
  <Accordion title="Warhead Chemistry">
    Ensure your input SMILES includes the appropriate warhead structure. For acrylamide-based inhibitors, use the ethyl-substituted amide form rather than the reactive acrylamide.
  </Accordion>

  <Accordion title="Residue Selection">
    Common covalent modification sites include:

    * Cysteine (SG atom)
    * Serine (OG atom)
    * Lysine (NZ atom)

    Verify the target residue number matches your protein sequence.
  </Accordion>

  <Accordion title="Current Limitations">
    Covalent inhibitor modeling is currently available only in Sandbox mode. Design Projects support for covalent inhibitors is planned for future releases.
  </Accordion>
</AccordionGroup>