Receptor-drug interactions stereochemistry

The SAR is also determined at the level of stereochemistry of interaction. In principle, three limiting situations can apply to the stereochemistry of drug-receptor interactions the enantiomers may not differ in activity the species may differ quantitatively or they may differ qualitatively. 

Stereochemistry of interaction has long been recognized in drug-receptor interactions and Pasteur very explicitly recognized that different stereoisomers could have very different physiological properties ... 

One of the critical factors associated with drug—receptor interactions is the three-dimensional structure of both the drug and receptor molecules. Efficient interaction between a drug and its receptor depends not only on the absolute and relative positioning of groups in space but also on the ability of the molecule to modify its shape by rotating about single bonds. These aspects of chemical structure are known as stereochemistry and conformation and are the topics covered in this chapter. 

In order to form a crystal, molecules must aggregate in an orderly manner. This implies that intermolecular interactions have occurred in specific ways. It therefore follows that the crystal structure per se contains information on preferred modes of binding between the molecules in the crystalline state. In this Chapter we show how information on the most likely stereochemistries of interactions between functional groups in different molecules can be extracted from the three-dimensional coordinates of atoms listed in reports of crystal structure determinations. Three-dimensional structural data on binding stereochemistry may also be obtained from X-ray diffraction studies of the binding of small molecules to crystalline proteins and other macromolecules. These two types of information can be used, for example, to predict how drugs will interact with their biological receptors. 

Similar to many other cases of biologically active compounds, stereochemistry influences the pharmacological effect of a chiral drug. This can be explained by the fact that there is only one energeticaUy favorable (specific) interaction of an active molecule with its receptor, both being chiral structures. Qualitative and quantitative differences are caused by different receptor affinities as demonstrated in Fig, 1 (1). The metabolism (biotransformation) of drugs is mainly caused by enzymes, which are chiral macromolecules and discriminate between substrate molecules of different stereochemistry, This may result in metabolites of different activity and in different pharmacokinetics, resorption, and excretion. Therefore, racemic drugs should be looked on as a 1 1 mixture of two different compounds. 

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