Hyper Design

An introduction to the AI-based design feature, which is the core of Hyper Design, and instructions on creating designs yourself.

In this tutorial, we will use Hyper Design to reproduce the hit-to-lead optimization process of imatinib (also known as Gleevec), a Bcr-Abl kinase inhibitor.

This tutorial uses the complex Abl kinase domain and imatinib, which has the PDB ID 2HYY. (Importing Protein)

1. When you import PDB ID '2HYY' in the Protein structure tab, you can see all four domains of chains A, B, C, and D in the Structure Information. Because they have the same Abl protein structure and have the same binding site, only Chain A will be kept. To clear other chains (B,C,D), you can uncheck their checkboxes. If your binding site of interest involves two chains, please check both.

2. Check A-STI-600 in the Ligand of Binding Site tab. Confirm your binding site in the 3D viewer by clicking on the magnifying glass icon.

To conduct Hyper Design, a hit compound would be used as the starting point.

1. In this tutorial, the initial structure of imatinib is used for hit-to-lead optimization. To register molecules, you can use the By Drawing option to add a molecule list.

   Initial structure smiles: C1C=NC=C(C2N=C(NC3C=CC=CC=3C)N=CC=2)C=1

2. After registering your molecule, calculate Hyper Binding using the Hyper Binding.

1. You can evaluate the initial structure's binding pose via 3D Viewer and obtain information for optimization.

• Looking at box 1, you can see that the prediction was correct by comparing the X-ray structure of imatinib in 2 with the predicted most stable binding structure of the initial active compound in 3.

• The hit compound forms a hydrogen bond with the hinge residue (MET318), which is the most important feature of the kinase inhibitor.

• An empty space is found on the right side of the binding site surface.

If the initial active compound is much smaller than the binding site, the predicted binding structure may be less accurate. The more accurate the initial binding prediction, the more likely you will achieve correct optimization and better results.

In the following procedure, new R-Groups will be added or replaced in the empty space of the binding site for hit-to-lead optimization.

Click Start in the Hyper Design column.

The very first page you see in Hyper Design when you click the start button in the Hyper Design column.

Hyper Design page icons.

1. Select all

2. Hyper Binding: Calculate Hyper Binding calculation for the selected molecule. This calculation does not apply to AI-designed molecules.

3. Hyper ADME/T: Calculate Hyper ADME/T calculation for the selected molecule.

4. 3D View: If you want to see the binding pose or other kind of 3D structure information, you can click and see the poses.

5. Bookmark: If you want to see only bookmarked molecules, click it.

6. Set card information: Set the field information displayed on the molecule card. For more details, click here.

7. Zoom Out

8. Zoom scale

9. Zoom In

10. Center your molecule

11. Select molecule.

12. Bookmark molecule.

13. Settings: View details, view AI molecules, delete molecule.

By clicking the + button, you can access the Hyper Design page.

There are three options that you can use in Hyper Design.

AI Design

Custom Design

Design Results

Hit-to-lead optimization will be conducted and explained on each page.