2D depiction of fragment hierarchies

Abstract

Drug discovery projects often involve organizing compounds in the form of a hierarchical tree, where each node is a substructure fragment shared by all of its descendent nodes. A method is described for producing 2D depiction layout coordinates for each of the nodes in such a tree, ensuring that common fragments within molecular structures are drawn in an identical way, and arranged with a consistent orientation. This is achieved by first deriving a common numbering scheme for common fragments, then using this scheme to redepict each of the molecules, one fragment at a time, so that common fragments have common depiction motifs. Once complete, the distinct root branches can be overlaid onto each other, after which all of the fragments and whole molecules have a common layout and orientation. Several methods are described for preparing visual representations of molecular structure hierarchies alongside activity information. Combining high level tree display and structure depiction showing common features readily facilitates insight into structure-activity relationships.

Figure 1

(a) shows the fragmentation sequence for four molecules which share a common root, which are grouped according to common fragments, while (b) shows the corresponding tree representation, which subsumes adjacent, analogous fragments into individual nodes.

Figure 2

For the pyridine root fragment, there are multiple ways to map the branches to each other, which are not of equal quality.

Figure 3

Shell patterns for substituents of disubstituted benzene fragments.

Figure 4

Stepwise assignment of a common numbering system, for a fragmentation tree consisting of 4 molecules.

Figure 5

Fragmentation tree where molecule coordinates are obtained by unconstrained depiction layout.

Figure 6

Same fragmentation tree as shown in Figure 5, after the colligative depiction layout procedure has been applied.

Figure 7

Orientation patterns for 9 root fragments. The numbers indicate how many structures are contained in each group. Hydrogen bond donors are tinted blue; acceptors are tinted red.

Figure 8

(a) Single root fragment and a selection of its immediate descendents. (b and c) Selected child of the root fragment and a selection of their descendents.

Figure 9

Dendrogram-style fragment tree layout, arranged onto a disk. The background color reflects activities of close-by fragments.

Figure 10

Portion of a dendrogram fragment display, with selected leaf nodes indicated.

Figure 11

Selected core fragments of COX2 inhibitors.

Figure 12

Structurally related COX2 inhibitors.