J. Chem. Inf. Model. 2010, 50, 37–46 37 2D Depiction of Fragment Hierarchies Chemical Computing Group, Inc., 1010 Sherbrooke Street West, Suite 910, Montre´al, Que´bec, Canada H3A 2R7 Alex M. Clark* Received September 16, 2009 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. INTRODUCTION A cornerstone of ligand optimization in drug discovery research is the comparison of activity and property data for a collection of molecules which are related by similar structural cores.1 In order to rationalize the relationship between structure and activity, it is often beneﬁcial to organize the structures in the form of a hierarchical tree. Structures with a common core fragment are arranged in branches, in which each parent fragment is a smaller, pared- down substructure that is common to each of the children. If the tree is well constructed, considerable insight can be gained regarding which core fragments and which peripheral substituents are responsible for the properties of interest, such as binding afﬁnity against some number of protein targets, toxicity, and relevant physical properties. Given a collection of arbitrary molecular structures, there is typically no single unambiguous way to arrange them in a tree such that each parent node is a substructure of all its children. If the molecules happened to be synthesized in a particular sequence, such as by introducing a variety of substituents in a stepwise fashion to some number of similar core fragments, it may be sensible to produce a fragmentation tree which is based on the synthetic procedures. Or, if a set of common scaffolds is already known, it may be sensible to start with these scaffolds as the root fragments, and from these, construct the descendency hierarchy. If the collection of molecules has signiﬁcant structural similarity, but no speciﬁc information about common substructures is available, then algorithms exist for estimating which parts of a structure are most scaffold-like. These can be used to generate a fragmentation sequence which can then be expressed as a tree.2 While the fragmentation techniques have been well developed, one part of the process remains conspicuously * To whom correspondence should be addressed. Phone: +1 514 393 1055. Fax: +1 514 874 9538. E-mail: aclark@chemcomp.com. undocumented. A fragmentation tree of molecules with similar common scaffolds is signiﬁcantly less informative if the 2D coordinates of the molecular diagrams are not arranged such that common fragments are drawn with a common layout and uniform orientation. Molecular structures are often sketched by chemists showing a standard orientation when structures are added to a database, but this is not always the case. For a small group of structures, or for a rare showcase example, it is typically not a Herculean task to manually ensure that all of the fragments are properly drawn and aligned. For larger collections, or if charged with the task of regularly regenerating this data, one would at least begin to feel like Sisyphus. Unfortunately, even if a good 2D depiction algorithm is already available, the procedure of generating 2D layout coordinates that honor common frag- ment ancestry, with group layout decisions made in the context of the global optimum, is not trivial. In this work, a method will be described for obtaining 2D coordinates suitable for structure diagrams, which are chosen for both independent aesthetic appeal and for clearly showing the common substructure patterns by means of layout and orientation. Also discussed are higher level presentation methods for making use of the structure-activity informa- tion, which is contained in the fragmentation hierarchy. In the following section, methods will be described for generating a fragment tree, mapping sibling fragments onto each other in an optimal way, then using this mapping to guide the 2D depiction process. The results section will describe methods of presenting this information in the context of examining structure-activity relationships. METHODS 1. Fragment Generation. For each molecule in the data set, it is necessary to propose a scheme whereby the molecule is peeled away in some number of steps, such that the last remaining fragments are the most scaffold-like. The deﬁnition 10.1021/ci900350h  2010 American Chemical Society Published on Web 12/29/2009