Automated Drawing of Structural Molecular Formulae Under User-Defined ConstraintsIntroductionThe 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. For additional information and application scenarios, please visit BioSolveIT. New ApproachFor this problem, we developed an algorithm [1] 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 mercapto-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. This algorithm creates drawings of small organic molecules under constraints in the order of hundred structures per second. Results
As an example we used angiotensine-converting enzyme (ACE) inhibitors to manually imposing constraints. The figure shows the output after manually adjusting the constraints as to reflect the preservation of the pharmacophore points. The pharmacophore pattern -which consists of two metal-complexing groups plus a carbonyl group- is preserved throughout the structure diagrams, and non/trivial functional groups for the pharmacophore become much more obvious. The arrows indicate the imposed constraints to be met.
Benzodiazepines drawn without constraints (figure 4a) and with the compound in row three, column three as the reference (figure 4b); all others have been drawn with the constraint of being aligned according to Feature Trees matches with respect to the template compound.
Tricyclic neuroleptics, drawn without constraints (figure 5a) and drawn under Feature Tree constraints using compound in row two, column one as reference (figure 5b): If it exists, the tricyclic moiety is preserved to be oriented in the upper right part of the respective square. If it does not, the user obtains fragments that -on the Feature Trees level- align to the tricyclic fragment, for example the compound in row four, column four at the respective site. For reasons of better visibility, no arrows indicating the constraints have been drawn here. Literature[1] Fricker, P., Gastreich, M., and Rarey, M.: Automated Drawing of Structural Molecular Formulae under Constraints, JCICS, 2004, 44, 1065-1078 [2] Rarey, M., and Dixon, J.S.: Feature Trees: A new molecular similarity measure based on tree matching, J. Comput.-Aided Mol. Design, 12, 471--490 (1998) |
