Tutorial Overview
In these tutorials, we will walk you through the steps required to generate such ideas as a starting point for a lead optimization workflow.
Figure 1. An example of a use case for generating a focused library for lead optimization.
Workflow at a Glance
The key inputs for these idea generators are a scaffold or molecule from which to build and a reaction and reagent database that has been created from:
A set of building block structures with unique IDs.
A reaction and reagent definitions file that contains the logic for:
Identifying reagents for particular transformations.
Processing reagents along with input scaffolds to generate product structures that would be created by the reaction(s) of interest.
The complete workflow is summarized in Figure 2.
Figure 2. Workflow describing the process of creating virtual analogs using generative floes.
The definitions file contains information about chemical moieties that are necessary for a transformation to occur, as well as moieties that would interfere with chemical reactions. In this way, the floes that leverage these definitions should produce compounds that have reasonable synthetic accessibility. The definitions file also contains SMIRKS for each defined transformation, which controls how to assemble reagents and disassemble products.
Figure 3. Logic contained within the reaction definitions file.
All generative floes in the package require first creating a Reaction & Reagent Database and then using the floes to generate product structures.
Focused Library Floes for Generative Design
Four main floes can be used for the Generative Design floes, differing primarily in the type of input that is provided to the floes.
- Focused Library – Core Input
Input: Core with up to four attachment points. This floe processes reagents in the database with a half-reaction and joins any fragments.
- Focused Library – Molecule Input
Input: Molecule. This floe detects synthetic handles and enumerates products using compatible reagents.
- Focused Library – Synthon Analogs
Input: Molecule. This floe detects and applies one-step retrosynthetic disconnects, then enumerates products using complementary compatible reagents with resulting synthons.
- Focused Library – Reagent Join
Input: Molecule. This floe retrieves and applies the selected reagents from the specified Reaction & Reagent Database to a user-specified site on a lead molecule.
In these tutorials, we will run the Focused Library – Core Input and Focused Library – Molecule Input Floes. Please note that if all focusing parameters are set in specific ways, similar results should be obtained using each of these floes.
These tutorials cover the following:
Creation of a reaction and reagent database
Inspection of the generated database
Generation of focused libraries using the generated database
They were developed using the Mcule Building Blocks catalog (Mcule Building Blocks, accessed 8/28/2024). At the time of writing, this catalog contained nearly five million building blocks. The resulting database can also be utilized in projects outside of the tutorial.
For each tutorial, follow these steps to find the floe.
Proceed to the Floe page using the blue navigation bar.
Click on the Floes tab.
From the Categories Floe Filters, click on the ‘Packages’ drop-down to expand the list of packages, then select the OpenEye Generative Floes Package.
A list of generative design floes will now be visible to the right. Click on the desired floe.
Alternatively, you can enter Reaction & Reagent Database or Focused Library in the search bar.
Click “Launch Floe” and a Job Form will pop up. Specify the parameter settings as indicated.
Click “Start Job” when you are ready to run the floe.