Reaction-Based Enumeration Panel

Using the Reaction-Based Enumeration Panel

The purpose of this tool is to generate structures in which parts of the chemistry are varied while others are held fixed. The generated structures can then be evaluated for suitability as drug candidates (or for any other purpose). The use of a reaction scheme in the enumeration of these structures, based on available reagents, addresses the issue of synthesis of the resultant drug candidates. This is in contrast to other enumeration methods, where the synthesis of the resulting compounds is not taken into account at all, and may produce structures whose synthesis is difficult or for which a synthetic route has to be found. The reagents (fragments) are taken from the eMolecules building block library. For information on creating and preparing custom reagent libraries, see Creating Reagent Libraries - Best Practices.

The panel provides three ways of defining the synthetic route, or pathway. The first involves an analysis of a molecule to identify a reaction that could be used to produce it. This analysis can be applied recursively, so that a reaction that generates one or more of the reactants can be identified. The second involves constructing a sequence of reactions from a list of standard reactions that leads to the desired product. The third is to sketch the reaction sequence, which is useful if steps in the reaction are not in the list of standard (or user-defined) reactions.

Once the pathway is defined, a set of reactants can be assigned to each variable group for each prototype reactant. These reactants are stored in libraries; a standard set of reactant libraries is supplied, but you can create your own and use those. The supplied libraries are taken from catalogs of commercially available compounds. Finally, the enumeration is performed, to produce a set of structures in which the desired groups are varied, whether they are peripheral groups on a core structure or the core structure itself, retaining the peripheral groups.

For information on running an enumeration of a reaction workflow from the command line, see enumerate_reaction_workflow.py Command Help.

For further background information, see Konze et al.

Reaction based Enumeration is also possible in Ligand Designer, see the Automated Reaction-Based Enumeration Panel for more information.

Where do the reagents come from?

The reagents used in Reaction-based Enumeration are taken from pre-built reagent libraries. By default, these libraries are derived from commercially available compound collections such as the eMolecules building block library. These reagents are curated and processed tu ensure compatibility with the reaction rules used during enumeration

How can I add my own reagents?

You can create and use custom reagent libraries from your own compound collections (for example, in-house building blocks). This is done by processing input structures (such as SDF files) into a reagent library format that is compatible with the enumeration workflow. Custom libraries can be used alongside or in place of default libraries. Once prepared, they can be selected in the panel or set as default libraries for enumeration.

Where do the reactions come from?

The reactions available in the panel come from a predefined set of reaction rules that describe how reagents can be combined. These include commonly used chemical transformations and designed to ensure that enumerated products are synthetically feasible. These reaction definitions can be used when automatically analyzing target molecules, selecting reactions from standard list, or building multi-step reaction pathways.

How can I add my own reactions?

In addition to the predefined reactions, you can define and use custom reaction rules. This allows you to model and incorporate custom reactions into workflows by either adding them to the reaction library or using them when constructing or sketching reaction pathways. This is particularly useful for specialized reaction types.