Generation with macrocyclization

Our chemistry-driven algorithm builds molecule fragment by fragment following the rules defined by organic reaction templates, including macrocyclization reactions. As a result, Makya allows the user not only to grow molecules in a linear manner, but also to generate macrocyclic compounds, from scratch as well as from an advanced intermediate. 

Illustration of a cyclization step that Makya can perform during molecule generation.

For more information, please check our paper:

Clarisse Descamps, Vincent Bouttier, Juan Sanz García, Maoussi Lhuillier-Akakpo, Quentin Perron, Hamza Tajmouati, Growing and linking optimizers: synthesis-driven molecule design, Briefings in Bioinformatics, Volume 26, Issue 5, September 2025, bbaf482, https://doi.org/10.1093/bib/bbaf482

Set-up

To generate macrocyclic compounds:

• Create a new Fragment Growing generator;

• In the "Exit Vectors" tab, in the Macrocyclization section, select a cyclization option:
  • Allow AI-based cyclization: The generator will decide when to apply a cyclization step, if it deems it necessary;
    • This is great if you are open to generating macrocyclic as well as linear molecules.
  • Force AI-based cyclization: The generator will always apply a cyclization step, and will decide when to apply it;
    • This is a good option if you want to see only macrocyclic compounds, while being open to a variety of structures.
  • Force expert-based cyclization: The generator will always apply two generation steps, and the second and final one will be a cyclization step.
    • This is the best option if you want to see only macrocyclic compounds and have a clear idea of the structure they should have. 

In case of expert-based cyclization, it is necessary to specify your starting fragment and select two exit vectors. A building block will be selected (from our catalogue and commercial building blocks) and plugged on the exit vector #1 as a linker; then, ring closure will be performed between exit vector #2 and a new endpoint on the linker.

Guide: How to select a proper Exit Vector 

The macrocyclization option is compatible with the entire optimization toolbox of Fragment Growing generators: you can select QSAR Models, 3D parameters, a reference chemical space,... to guide your generation.

Size of the ring

The Products panel in the Generators module includes a feature that enables users to specify the ring size of their macrocycles, providing greater flexibility and precision in their molecule design.

Defining the Ring Size

Navigate to the Products panel within the Generator’s module.

Under the Iktos descriptors, you can specify the minimum and/or maximum number of atoms for the ring size in the Macrocyclization: size of the ring option.

Min: Enter a value equal to or greater than 8. The module does not support ring sizes smaller than 8.

Max: Specify the upper limit for the ring size.

Example

In the generation below, we set up a ring size constraint at ≥ 12, meaning we're forcing the generator to find molecules whose macrocyclic ring contains at least 12 atoms. 

Example of generated molecules: