Thank you for answering our questionnaire! Based on your answers, we have provided our team's recommendations to help you properly set up Makya for your project.
Your answers
- I want to modify the center of my molecule, keeping the external branches fixed
- I want to stay close to a reference molecule or dataset
- No, I don't have data yet, I am starting a new project
Given the requirements of your project, we recommend setting up a Fragment Linking generator guided by a reference chemical space.
1. Selection of the generator
The Fragment Linking generator can be used for generating compounds by proposing new linkers and/or scaffolds between two building blocks and their reaction centers. It is purely chemistry-driven so a good understanding of organic chemistry is required. By defining the exit vectors (where the chemistry will take place), the generator will search for commercial building blocks which can react in such a position.
For example, given a couple of building blocks: A and B and their reaction centers (exit vectors) -NH2 and -Br respectively, the fragment linking generator will propose novel compounds by attaching new scaffolds at those centers while keeping the rest of the building blocks intact.
2. Construction of a Chemical Space
Chemical spaces are used in Makya to guide molecule generation in a direction of the user’s choice. Generators that are given a reference chemical space optimize the Tanimoto similarity of generated compounds to the chemical space. Playing with the input space can strongly influence the generator’s outcome. In particular, not only can you include data from your project or from the literature (such as a chemical series that you wish to expand), but you can also include your own ideas and designs.
3. Step by Step setup
Step 1: upload your reference chemical space in Makya
Note: this step is not necessary; you can also create your custom chemical space during the generator set-up, and even use the sketcher to draw your molecules (see Step 2, Chemical Space).
- Prepare a .csv or .sdf file with a SMILES column that lists all the molecules you want to remain close to.
- To upload your reference dataset, follow the steps described in the documentation: Datasets.
- Requirements: your dataset should not contain columns without any values or without a column title.
- Note: Makya automatically cleans the dataset. In particular, chirality is removed. For more information, see the documentation.
Step 2: set up your Fragment Linking generator
A description of the Fragment Linking generator and of the setting-up steps is provided in the documentation: Fragment Linking generator. You can also find examples in our use-cases: for example, Scaffold Hopping with the Fragment Linking generator.
- Create a new Fragment Linking generator in the Generation tab of your project. The generator set-up page appears.
- In the Exit Vectors tab, enter the two external branches of your molecule.
- The fragments should not contain any charged atoms, as protonation is performed directly inside Makya.
- It is important to input fragments that are suitable building blocks for chemical synthesis (for example, brominated or chlorinated fragments, or molecules with an OH to form an ester), as the Fragment Linking generator is a chemistry-based generator trained on chemical reactions.
- After having entered your fragments, select the exit vectors by clicking on Set and inputting the atoms ID.
- Make sure to select all the atoms that will be involved in the reaction.
- In the Chemical Space tab, select the dataset of your project.
- If you have not uploaded a dataset in the previous step, you can also create your own chemical space here: click on Create Chemical Space and write your SMILES, or draw your molecule using the sketcher (pen icon).
- The similarity to this chemical space will be an element of the overall fitness function that will be optimized during molecule generation. It ensures that you will stay close to your project molecules.
These are the minimal steps needed to fit the requirements of your project. If you want to add more constraints on the generation, you can do so during the set-up of your generator. For example, you can add scorers with RDKit descriptors. They will score your molecules post generation and help you filter the results. You can also set up 3D ligand-based parameters so as to generate molecules that are close to one of your reference molecules in 3D.
Step 3: run the generator and analyze your results.
- To run your generator, go back to the Generation tab and click on Run.
- You can see the first generated molecules while the generation is still running. Check that there is no error in your set-up and that the generated molecules look conform to the requirements of your problem.
Once you have enough molecules, you can use the Parallel Coordinates to filter the molecules based on scores such as the Iktos Ranking or Similarity to your chemical space. For more information on the visualization, analysis and export of your results, check the documentation: Visualisation and Analysis of Generated Molecules.
For any questions, contact your Application scientist.