4.4.6. Reaction Transforms From Pairs
ADMET Predictor allows you to convert selected pairs into reaction representations that can be used to generate new molecules via Combinatorial Transforms (DESIGN>>Combinatorial Transform). This approach has an advantage over the default approach in that the resulting reaction transforms are related to a particular set of data rather than taken from a generic, predefined list. Furthermore, pairs associated with improvements in a key molecular property may yield transforms that tend to produce the same improvement in property when used to generate new molecules. Note that in the subsequent discussion the terms reaction, transform and rule are used interchangeably.
A reaction that is generated from a pair describes the structural transformation that is represented by that pair. In other words, a reaction is generated such that when applied to the molecule on the left side of the pair, generates a product molecule identical to the one on the right side. Although this concept appears rather straightforward, it is not particularly useful to have a reaction that can be applied only to one particular molecule. If the reaction is to be used for generating analogs, it should be applicable to other molecules structurally similar to the one used to generate the reaction. It must not, however, be so general that it applies to molecules that are not structurally similar to that starting molecule. The challenge of reaction generation is therefore to produce reactions that are general enough to apply to a variety of different molecules but specific enough to prevent their application to highly dissimilar motifs.
Each reaction transform rule can be thought of as having two components: a substructure that must be present in a molecule in order for the reaction to be applied to it, and a set of instructions describing the structural transformation that occurs. The second component is determined by the structural change in each pair, but the first component will depend on how general the reaction is intended to be. To make a more general reaction, the substructure should likewise be more general. This is discussed more fully below.
To generate transform rules, you must select one or more pairs and choose PAIRS>>Generate Transforms.
This launches the Export pairs as reaction transforms dialog, which provides a number of options that control the manner in which each pair will be converted into one or more reaction representations. The three most important options control the specificity of the reactions. The first of these is the minimum number of atoms contained in the substructure defining the reaction. The smaller the number, the more general the reaction will be. Note that when the number is smaller than the number of atoms in the original molecule (the left-hand molecule of each pair), there may be a large number of equally valid substructures that can be generated, and ADMET Predictor will attempt to generate a separate reaction for each one of them. The second option controls whether the reaction substructures require exact atom and bond matching (e.g., Carbon only matches Carbon) or whether atom and bond types can be ignored. The third option controls whether ring connectivity (i.e., whether bonds are ring bonds as opposed to chain bonds) must be exactly preserved, or whether differences can be tolerated. Activating these last two options yields more general reactions.