Most molecules relevant to life have chirality, a feature which means there are multiple geometric arrangements of an otherwise atomically identical compound. This feature gives a certain geometric asymmetry to molecules which may superficially look the same. Somewhere in the crucible of life, this asymmetry became systematic. Deoxyribose, ribose, lipids, and proteins took on a certain handedness within biological systems which may have been coincidental or may have been favorable some way energetically. In either case, chirality is a very interesting feature of chemical biology which should take a more central role in developing medicines. To be more specific, chirality is something that medicinal chemistry does not always look favorably upon. Introducing chiral centers into drugs often increases synthetic difficulty, requires more expensive reagents, requires more time to synthesize, and requires extra purification steps to separate enantiomers or diastereomers. To give credit where it’s due, my recent observations at American Chemical Society meetings suggest that industrial companies are definitely incorporating interesting chiral arrangements when optimizing lead molecules, however it’s hard to say how reflective what I saw was of the industry as a whole. The reason I wanted to bring this up is I strongly believe chirality is the missing link between why so many drugs continue to be derived from natural products.
Natural products often have many, many chiral centers. For nature, incorporating chiral centers is “easy” since all enzymes are chiral anyway. With chiral substrates, a much greater selectivity can be elicited for a target with any given substrate. An analogy of the selectivity of chiral substrates is a handshake. Hands are chiral, so a handshake is a process between 2 chiral entities, similarly to a drug-protein interaction. One can only shake hands properly with the same hand of both parties. A left hand to right hand handshake is awkward and uncomfortable. A molecule with many chiral centers takes this concept much further, into the atomic realm. A molecule with many chiral centers can only interact well with a small number of proteins, reducing the risk of side effects. Connecting this idea with the observation that most natural product-based medicines have fewer side effects relative to their achiral, synthetic counterparts brings one to the conclusion that chirality is a very important feature for medicines to have. Of course, other factors add to the safety of natural product-based medicines such as presence of balancing effects of the minor constituents with a natural product. A strong agonist will often be found mixed in with weaker antagonists and vice versa, generating a controlled modification of the biological pathway. The ideas I have just presented are yet to really be proven, but that won’t stop people from trusting natural products over synthetic drugs, even when evidence of safety and efficacy is “overwhelming.” There is something to be esteemed when it comes to why so many generations of humans turn to specific sources for healing. As chemists, we can come up with biophysically meaningful explanations for why, but until chemists capitalize on this knowledge, there will always be a gap in understanding.
