As we move on to pharmaceutical applications of stereochemistry, we have to understand how in the first place our body distinguishes different drugs from one another. This is where enzymes come in. The biological catalyst is very specific in its active site, such that it only binds to very specific groups on the drug molecule in a very specific order. This allows enzymes to distinguish not only stereoisomers of chiral molecules but also identical groups in prochiral molecules.
To illustrate this, we use the ‘three-point attachment’ model proposed by Ogston in 1948 [1]. Over here, we zoom into the tetrahedral carbon which is going to attach to the enzyme IV with binding site A’, B’ and C’. These binding sites are very specific and will only bind to A, B and C, respectively, in the particular geometry shown. In chiral enantiomers I and II, it is clear that only molecule I will best be able to attach to enzyme IV while molecule II simply does not have the optimal geometry. For molecule III which have two identical group A, the binding would still be specific. In the orientation shown below, molecule III has the same three groups as molecule I facing the enzyme in the correct order. However, if the orange face is to be facing the enzyme instead, molecule III would not be able to bind to enzyme IV as it no longer has the correct geometry.
In fact, this is also true for other regulatory proteins such as receptors. Since much of biological activities in our body are regulated by stereospecific proteins, stereochemistry is a major consideration in pharmaceutical chemistry as we will need the drugs to be able to bind to the correct protein to work, and we also have to make sure that the drugs do not end up binding to the wrong proteins and wreak havoc in our body.
References
- Ogston, A. G., Interpretation of Experiments on Metabolic Processes, Using Isotopic Tracer Elements. Nature 1948, 162 (4129), 963-963.