Patrick Fricker, Marcus Gastreich, and Matthias Rarey.

The growing number of applications dealing with large sets of molecules from virtual screening via de-novo design and library design to HTS analysis and lead optimization approaches need to present molecule structures to the user in a convenient way to browse through at least tens of structures in a short time.

To obtain a fast visual impression of such a large set of molecules, 2D molecule diagrams are one of the favored depictions. In such an environment, it is desirable to influence the layout of the diagrams depending on the application. Usually, the molecules of interest show some relationship to each other: for example, in a combinatorial library, they have a common core structure, in virtual screening to a given query molecule and in HTS analysis they are similar to each other forming clusters. Here, it is necessary to draw the molecules in a way that the relationships among them become visible for the user of the software.

We present a new algorithm for automated creation of 2D structural formula of molecules [1]. The algorithm is based on the classical scheme of a drawing queue placing the molecular fragments in a sequential way. We extended the concept of prefabricated units developed for complex ring systems to automatically created drawing units for chains and rings which will then assembled in a sequential fashion. In order to deal with combinatorial libraries, the drawing algorithm was modified such that the common core is uniquely oriented in all drawings.

Further on, we give an algorithm which enables the drawing of 2D structural formula under directional constraints assigned to a subset of bonds. The directional constraints are applicable to different types of scenarios. It is feasible to let constraints be automatically derived by software tools for molecular design. One such automated application of the constraints which has been implemented employs Feature Tree [2,3] similarity matchings. Such matchings give pairwise alignments of respective pharmacophoric groups, for example the OH-group of one compound may often match the mercaptane-functionality of another. Utilizing this information as a constraint for drawing leads to a directed depiction of the molecule, from which the user can more easily re-establish the similarity of a set of compounds with a common pharmacophore.

The introduced method was evaluated on the NCI cancer library for performance and coverage. For drawing of common-core structures, the method was applied to a combinatorial library based on the Ugi reaction. The directional constraints in combination with the Feature Trees were used to draw diagrams for angiotensine-converting enzyme (ACE)-inhibitors. The drawings clearly show the automatically identified similarities within the compound set which are in agreement with a known pharmacophore for this inhibitor class. This algorithm creates drawings of small organic molecules under constraints in the order of hundred structures per second.

[1] Fricker et al., Automated Generation of Structural Molecular Formulae Under User-Defined Constraints, in preparation
[2] Rarey et al., Feature Trees: A new molecular similarity measure based on tree matching, J. Comput.-Aided Mol. Design (1998) 12, 471-490
[3] www.BioSolveIT.de/FTrees