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|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.
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.
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.
Schwab, C.H; Gasteiger, J.
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