Prostereoisomerism and biological activity: possible implications for drug design


Abstract: Prostereoisomerism (PIM), representing a subgroup within the achiral class of molecules, is manifested in a chiral environment. Although this is regardless of the orientation of the prostereoisomeric (PIC) molecule, PIM is manifested most emphatically in relation to a chiral surface (`two-dimensional chirality'). Then PIM is tantamount to `de facto chirality' as attachment of the PIC molecule to the surface leads to diastereomeric possibilities (cf. Ogston's hypothesis). Furthermore, the formation of host--guest complexes requires a steric complementarity between the component molecules. The fact that the weak dispersive forces involved therein require an optimum distance implies a `snugness of fit' criterion. This further implies that a chiral host prefers a chiral guest molecule, and a chiral surface prefers a PIC molecule as substrate. These indicate a general stereochemical criterion for host--guest complexation that is particularly relevant to the case of biological receptors. Indeed, a survey of several known achiral drug molecules indicates that they generally possess at least one PIC moiety, lending credence to the above arguments. Thus, it would appear that PIM represents a maximum level of molecular symmetry for biological activity to be manifested efficiently.

Keywords: Host-guest, Ogston, prochiral, 2D-chirality, van der Waals

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