Mechanisms of Stereoselective Binding to Functional Proteins

Abstract

The three-dimensional structure of a drug molecule determines and evolves its biological properties at a given receptor. The spatial configuration of a molecule results from the connectivity of the atoms composing the molecule under consideration. If this spatial configuration encodes for asymmetry, the molecule gives rise to optical activity and two enantiomers exist. Without breaking bonds such a pair of chiral molecules cannot be transformed from one to the other form (neglecting special situations of slowly converting atropisomers; see also Chap. 4, this volume.). As long as such enantiomers are exposed to an achiral environment they possess identical properties. However, once presented to a handed surrounding, image and mirror-image will be recognized differently and will produce different effects. Receptors, for example enzymes, often being the target of drug molecules, create a chiral environment. They are constructed from chiral building blocks, such as L-amino acids. Other targets, e.g., DNA, RNA, or ribozymes, are composed by D-ribose or D-desoxyribose as chiral building blocks. Furthermore, as a whole, these molecules adopt conformations that correspond to handed objects. Accordingly, a different biological response can be expected once the two mirror-symmetrical molecules bind to such a chiral receptor. For example, the flavor of the two enantiomeric forms of carvone and limone (1 and 2 in Fig. 1) create quite different smelling characteristics once binding to the corresponding receptors (Friedman and Miller 1971).