Drug Design - Perception of Molecular Similarity with a Genetic Algorithm


The maximum common substructure (MCSS) is a similarity measure that allows the study of a variety of chemical problems. The relationships between structure and biological activity, between the target of a synthesis and appropriate starting materials as well as biosynthetic pathways can be investigated by the determination of the MCSS or the three-dimensional MCSS. The determination of the largest substructure contained twice in a single molecule allows one to derive synthesis precursors that can be used several times to make a synthesis short and convergent.

The determination of a MCSS is a computationally expensive task, that is solved by a genetic algorithm, an optimization method that imitates the adaptation methods of nature. Molecular recognition at the receptor binding site depends on the exact conformation of a biologically active compound. Thus, the recently developed version of the genetic algorithm considers conformational flexibility of the molecules. A hybrid method including two main optimizations has been applied:

  • rotation around single bonds by genetic operators
  • the genetic algorithm is combined with a steepest descent optimizer that induces a target oriented superposition of the atoms.

The application of the hybrid method leads to an increased size and to an improved geometrical fit of the superposition. Thus molecular similarity can be recognized.


M. Wagener, J. Gasteiger,
Die Bestimmung größter deckungsgleicher Teilstrukturen mit einem genetischen Algorithmus: Anwendung in der Syntheseplanung und zur strukturellen Analyse biologischer Aktivität.
Angew. Chem., 1994, 106, 1245-1248.
The Determination of Maximum Common Substructures by a Genetic Algorithm: Application in Synthesis Design and for the Structural Analysis of Biological Activity.
Angew. Chem. Int. Ed. Engl., 1994, 33, 1189-1192 (1994).

S. Handschuh, M. Wagener, J. Gasteiger,
Superposition of Three-Dimensional Structures Allowing for Conformational Flexibility by a Hybrid Method.
J. Chem. Inf. Sci., 1998, 38, 220-232.


Alexander von Homeyer