Drug design conformational constraint

In the enkephalin studies we began to see how theoretical techniques can be used to generate conformations of related molecules. With the results from GnRH and vasopressin we saw how flexible these molecules are and how the conformational fluctuations and dynamics of these molecules can be studied. We also saw how the relative stabilities of conformations of a molecular fragment can be influenced by conformational constraints of the whole molecule. In the following section we will present some ideas on how these calculations can be incorporated into a conformational based approach to drug design. 

Knowledge of the receptor-bound conformation of a ligand is of great help in drug design. Constraints can then be introduced to encourage... 

The design of new drugs with improved activity is frequently based on the introduction of conformational constraints in order to freeze bioactive conformations of the molecules. For this purpose, a variety of conformationally constrained scaffolds, that can be functionalized with different pharmacophores, have been developed. In this context, carbohydrates appear to be ideal substrates due to their conformational rigidity and offer the possibility of different functionalization of their hydroxyl groups. (/) On the other hand, the introduction of an amino and a carboxylic group into the rigid structure of the carbohydrate, allows to obtain conformationally constrained peptidomimetics,... 

Maybe the most ambitious aspect of current conformational studies on pqjtides is the correlation to their biological activity, which is determined by the conformation of the protein when it is interacting with the receptor ( receptor-boimd conformation ). Systematic introduction of chemical modifications with predictable conformational effects in the strategy employed helped to identify the receptor-bound conformation. Retention of biological activity implies that the conformational constraints imposed by the alteration are tolerated by the receptor. Research in this field can be summarized by the expression rational drug design . 

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