Drug Design - Generation of Multiple Conformations

Addressing Conformational Flexibility

Most molecules of organic, biochemical or pharmacological interest can adopt quite a few conformations of nearly equal energy by rotation around single bonds. The interaction of the molecule with its environment, e.g. with the binding site of a biological receptor, may determine which of these conformations is the preferred one. Therefore, conformational flexibility has to be taken into account in the development of new compounds with a desired biological or chemical property. Small ring systems are orders of magnitude more rigid than open-chain portions and therefore, the number of low-energy conformations is much smaller. Thus, in our rule and data based approach to addressing conformational flexibility, cyclic and acyclic molecules and fragments are treated separately.

Cyclic Structures

The 3D structure generator CORINA is able to perform a systematic conformational analysis for ring systems of up to a size of eight ring atoms. CORINA is using a list of different ring templates derived from statistical and empirical data to generate a set of different ring geometries. These ring templates are stored as lists of torsional angles, for each ring size and number of unsaturations in the ring, ordered by their conformational energy.

Acyclic Structures

The rule and data based program system ROTATE, was developed to explore the conformational space of acyclic parts in medium-sized (drug-like) molecules. The development of ROTATE was initiated in 1996 and has matured through a series of versions. Starting with a given 3D structure, ROTATE generates a set of multiple conformations by rotation around bonds, which are regarded to be rotatable. The program uses a set of rules and data derived from a statistical analysis of the conformational preferences of open-chain fragments in small molecule crystal structures. For this purpose the Cambridge Structural Datafile (CSD) obtainable from the Cambridge Crystallographic Data Centre was used.
This analysis led to sets of preferred dihedral angles for fragments consisting of four atoms with a central rotatable bond. These torsion angle patterns are stored in a library, the so-called Torsion Angle Library. Thus, ROTATE generates reasonable geometries which have been observed, rather than sampling local energy minima or generating conformations randomly.
The number of conformations drastically increases with the number of rotatable bonds. In order to restrict the number of generated conformers, while retaining a maximum of structural diversity, ROTATE offers two different methods for classifying the rotamers. Each class thus obtained is represented by a single conformation.


Schwab, C.H; Gasteiger, J.
Addressing Conformational Flexibility
Oral Presentation; 5th International Conference on Chemical Structures,
Noordwijkerhout, The Netherlands: Noordwijkerhout 1999.

Schwab, C.H.
Konformative Flexibilitaet von Liganden im Wirkstoffdesign.
Ph.D. Thesis; University of Erlangen-Nuremberg: Erlangen 2001.


Dr. Christof H. Schwab
CORINA and ROTATE can be obtained from Molecular Networks GmbH.
For further information please send a message to info@mol-net.de.