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.

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.