Problem: Starting from a reference molecule, how to generate novel molecules that are structurally and functionally similar in Makya?

In this scenario, we aim to design new compounds that maintain the pharmacophore features and 3D shape of a reference molecule, ensuring they are synthetically feasible and possess desirable drug-like properties.

Reference and Anchor Molecules

Reference Molecule (SMILES):
COC1=CC=CC(=C1)N1CCC2=CC(=CC=C12)C1CCOCC1
This molecule serves as the starting point for our design, providing the desired 3D conformation and pharmacophoric elements (see below).
Anchor Fragment (SMILES):
COc1ccccc1
The anchor represents a substructure of the reference molecule that must be preserved in all generated compounds (see below).

Step 1: Create the 3D Ligand-based parameters

Step 1: We will start by setting up a 3D Ligand-based scorer that can then be used to guide generation. To do so, simply click on the "3D LIGAND-BASED SETTINGS" tab, then create a 3D score by clicking on the + logo:

1. Reference molecule

A window appears that lets you enter the information (in the form of a SMILES or a SDF file) for your reference molecule.

If you have a preferred conformer for your reference 3D molecule, you can directly upload an SDF file.

NOTE: RDKit should be able to convert your SDF back to SMILES in order to score the generated molecules. Before uploading your file, please check that this is the case.

If you do not have a preferred conformer, or if this conformer can be generated by RDKit, you can simply enter the SMILES of your reference molecule (or use the sketcher tool by clicking on the pen icon). Makya will generate likely conformers and let you choose one.

In this example, we use this SMILES as the reference:

COC1=CC=CC(=C1)N1CCC2=CC(=CC=C12)C1CCOCC1

2. Anchor

You can then specify the anchor substructure. The anchor is a sub-unit of the reference molecule used as a reference point for 3D alignment.

IMPORTANT: This sub-unit has to be present in all the generated molecules for the 3D alignment to be done. With the Growing or Linking generators, please make sure that your generated molecules contain this part somehow (in the exit vector or the building block constraints).

We use this SMILES for the anchor:

COc1ccccc1

3. Conformer generation

Makya will then automatically generate up to 10 probable conformers, sorted by ascending energy.

You can choose the one you prefer using the arrows on top. For this example, you can select the first conformer.

If you want more conformer suggestions, you can click on the spinning arrows symbol.

4. Pharmacophore customization

Finally, you can specify the type and location of the pharmacophores you want to find in newly generated molecules. In this example, we put a stronger weight on the core aromatic ring.

Step 2: Create the generator

Step 2: We will now set up and launch our generator. On the project homepage, go directly to the "Generators" tab and click on New Generator. Under Generation Engine, select Fragment growing and click on Next.

On the following pages, specify the settings of the generator:

Exit Vectors: In the text field below "Enter SMILES", copy-paste the following SMILES:

COc1cccc(B(O)O)c1

This is the boronic acid that we will use as the starting point for our generation. Set the exit vector as shown on the image below.

NOTE: the Methoxyphenyl moiety is present since it is used as anchor in the 3D parameters.

3D Ligand based: Select the 3D ligand-based scorer that was previously set up and click on Save.

The generator is set and ready to run. Go back to the "Generators" tab, and the newly set up generator will show up. Click on the Run button for this generator. The progress bar will indicate the status of generation.

Step 3: Explore the generated molecules

Step 3: while the generation is still running, you can visualize the first results. The generated molecules are scored using the 3D Shape score and the 3D Pharmacophore. Molecules can be sorted using these scores.

By clicking on See details on any result, in the "3D shape" tab, the generated 3D conformation can be visualized.

By selecting several molecules and clicking on 3D Ligand Based Results in the top-right "View" module, you can superpose all the molecules simultaneously.