Drug Enantiomers and Chirality

Drug Enantiomers and Chirality

1. Definition & overview

• Chirality (Greek cheir, "hand") is the property of a molecule of being non-superimposable on its own mirror image, exactly as a left hand is not superimposable on a right hand — the molecule and its mirror image are distinct three-dimensional objects (Katzung 16e Ch.1, p.4).
• Stereoisomerism is the broad phenomenon of which chirality is the most pharmacologically important manifestation; Katzung explicitly equates the two in the drug context — "the phenomenon of chirality (stereoisomerism)" — because most clinically relevant stereoisomerism arises from chiral centres (Katzung 16e Ch.1, p.4).
• A drug molecule that is chiral can exist as enantiomeric pairs — two stereoisomers that are non-superimposable mirror images of each other (Katzung 16e Ch.1, p.4).
• The structural origin of chirality is an asymmetric (chiral) centre — most commonly a carbon atom bearing four different substituent groups, around which the four groups can be arranged in two distinct spatial configurations (Katzung 16e Ch.1, p.4; G&G 14e Ch.1 — "compounds with multiple chiral carbon atoms").
• Chirality is extremely common in drug molecules — "the phenomenon of chirality (stereoisomerism) is so common in biology that more than half of all useful drugs are chiral molecules" (Katzung 16e Ch.1, p.4).
  • This reflects the fact that the biological macromolecules drugs act on (receptors, enzymes, transporters) are themselves built from chiral building blocks (L-amino acids, D-sugars) and therefore present a chiral, asymmetric environment to any drug.
• Chirality is one of the fundamental physicochemical drug properties — alongside molecular size, shape, charge, and configuration — that determine the selectivity of binding to a target biomolecule (KDT 8e Ch.1; Katzung 16e Ch.1, "Drug Shape").
  • For a drug of molecular weight ≈100–1000 Da to bind selectively to only one or a few closely related targets, it must be "sufficiently unique in shape, charge, and other properties," and chirality is listed among the features (shape, size, configuration, chirality, charge distribution) that confer such selective binding (KDT 8e Ch.1, drug-molecule properties; Katzung 16e Ch.1, "Drug Shape," p.4).