Drug design receptor-bound conformation

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

Drug Design and the Receptor-Bound Conformation of Thyrotropin Releasing Hormone (TRH) Design and Synthetic Approaches Towards Rigid TRH Analogs. 

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 . 

Very often, it is unknown which conformahon of a flexible molecule is needed. For example, in drug design, we hunt often for the so-called bioachve conformation, which is the molecule in its receptor-bound state. In this case, any other experimental structure of the isolated molecule - in vacuum, in soluhon or in crystal - can be the wrong choice. 

In structure-based drug design, the so-called bioactive conformation (the preferred conformation in the receptor-bound state) of potential drug molecules is of special interest. Its prediction is a challenging and demanding task, even if structural information on the biological receptor is available. 

Until now, few studies have been reported that use NMR-derived structures directly for drug design efforts. The majority of these early applications involve determination of the conformation of ligands, bound to their receptors. Recently, however, accurate solution structures of proteins complexed with ligands have been reported which are useful in drug design efforts. 

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