Abstract
A new algorithm for multiple semi-flexible superpositioning of drug-sized molecules is described. It identifies structural similarities between two or more molecules. To account for the flexibility of a molecule, multiple conformers drawn from molecular ensembles generated by conformational analysis are used. To address the varying degree of similarity among the molecules, similar substructures present in different subsets of the molecules are identified.
All molecules are compared to a preselected reference molecule. Clique detection on the correspondence graph of two molecular structures is applied to generate feasible start transformations, which are used to compute common substructures. The results of these pairwise comparisons are efficiently merged using binary matching trees.
Despite considering the full atomic information for identifying multiple structural similarities, the algorithm is well suited as an interactive tool for exploring drug-sized molecules, and has been integrated into the molecular visualization package AmiraMol. The algorithm’s capabilities are demonstrated on two sets of molecules.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
McMartin, C., Bohacek, R.: Flexible matching of test ligands to a 3d pharmacophore using a molecular superposition force field. J. Comput. Aid. Mol. Des. 9, 237–250 (1995)
Jones, G., Willett, P., Glen, R.C.: A genetic algorithm for flexible molecular overlay and pharmacophore elucidation. J. Comput. Aid. Mol. Des. 9, 532–549 (1995)
Lemmen, C., Lengauer, T.: FLEXS: a method for fast flexible ligand superposition. J. Comp. Chem. 41, 4502–4520 (1998)
Handschuh, S., Wagener, M., Gasteiger, J.: Superposition of three-dimensional chemical structures allowing for conformational flexibility by a hybrid method. J. Chem. Inf. Comp. Sci. 38, 220–232 (1998)
Good, A.C., Hodgkin, E.E., Richards, W.G.: Utilization of Gaussian functions for the rapid evaluation of molecular similarity. J. Chem. Inf. Comp. Sci. 32, 188–191 (1992)
Grant, J.A., Gallardo, M.A., Pickup, B.T.: A fast method of molecular shape comparison: A simple application of a Gaussian description of molecular shape. J. Comp. Chem. 17, 1653–1666 (1996)
Lemmen, C., Hiller, C., Lengauer, T.: RigFit: A new approach to superimposing ligand molecules. J. Comput. Aid. Mol. Des. 12, 491–502 (1998)
Cosgrove, D., Bayada, D.M., Johnson, A.P.: A novel method of aligning molecules by local surface shape similarity. J. Comput. Aid. Mol. Des. 14, 573–591 (2000)
Hofbauer, C.: Molecular Surface Comparison. A Versatile Drug Discovery Tool. PhD thesis, Technische Universität Wien (2004)
Brint, A.T., Willett, P.: Algorithms for the identification of three-dimensional maximal common substructures. J. Chem. Inf. Comp. Sci. 27, 152–158 (1987)
Martin, Y.C., Bures, M.G., Willett, P.: Searching databases of three-dimensional structures. In: Lipkowitz, K.B. (ed.) Reviews in Computational Chemistry, vol. 1, pp. 213–263. Elsevier Science Publishers B.V., Amsterdam (1990)
Lemmen, C., Lengauer, T.: Computational methods for the structural alignment of molecules. J. Comput. Aid. Mol. Des. 14, 215–232 (2000)
Martin, Y.C., Bures, M.G., Danaher, E., DeLazzer, J., Lico, I.: A fast new approach to pharmacophore mapping and its application to dopaminergic and benzodiazepine agonists. J. Comput. Aid. Mol. Des. 7, 83–102 (1993)
Kirchner, S.: Ein Approximationsalgorithmus zur Berechnung der Ähnlichkeit dreidimensionaler Punktmengen. Diploma Thesis, Department of Computer Science, Humboldt University Berlin (2003)
Bron, C., Kerbosch, J.: Algorithm 457: Finding all cliques of an undirected graph. Communications of the ACM 16, 575–577 (1973)
Kabsch, W.: A discussion of the solution for the best rotation to relate two sets of vectors. Acta Crystallographica A 34, 827–828 (1978)
Thimm, M., Goede, A., Hougardy, S., Preissner, R.: Comparison of 2d similarity and 3d superposition. Application to searching a conformational drug database. J. Chem. Inf. Comp. Sci. 44, 1816–1822 (2004)
Veldhuizen, D.A.V.: Multiobjective Evolutionary Algorithms: Classification, Analyses, and New Innovations. PhD thesis (1999)
Fischer, A., Schütte, C., Deuflhard, P., Cordes, F.: Hierarchical uncoupling-coupling of metastable conformations. LNCSE Series, vol. 24, pp. 235–259. Springer, Berlin (2002)
Berman, H., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T., Weissig, H., Shindyalov, I., Bourne, P.: The Protein Data Bank. Nucleic Acids Res. 28, 235–242 (2000)
AmiraMol – User’s Guide and Reference Manual. Zuse Institute Berlin (ZIB) and Indeed - Visual Concepts GmbH, Berlin (2002), http://www.amiravis.com
Wexler, R.R., Greenlee, W.J., Irvin, J.D., Goldberg, M.R., Prendergast, K., Smith, R.D., Timmermans, P.B.M.W.M.: Nonpeptide Angiotensin II Receptor Antagonists. J. Comp. Chem. 39, 625–656 (1996)
Sadowski, J., Gasteiger, J.: From Atoms and Bonds to Three-Dimensional Atomic Coordinates: Automatic Model Builders. Chemical Reviews, 2567–2581 (1993)
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2005 Springer-Verlag Berlin Heidelberg
About this paper
Cite this paper
Baum, D. (2005). Multiple Semi-flexible 3D Superposition of Drug-Sized Molecules. In: R. Berthold, M., Glen, R.C., Diederichs, K., Kohlbacher, O., Fischer, I. (eds) Computational Life Sciences. CompLife 2005. Lecture Notes in Computer Science(), vol 3695. Springer, Berlin, Heidelberg. https://doi.org/10.1007/11560500_18
Download citation
DOI: https://doi.org/10.1007/11560500_18
Publisher Name: Springer, Berlin, Heidelberg
Print ISBN: 978-3-540-29104-6
Online ISBN: 978-3-540-31726-5
eBook Packages: Computer ScienceComputer Science (R0)