It is unsurprising that understanding of the mechanism of action of acetaminophen ranges from “poor” to “clear” (C&EN, July 21, page 31).
In general, a solute in a solvent may alter the activity of a target in two ways: direct interaction with the target or via indirect interaction with the target resulting from modified target-solvent interactions as a consequence of the presence of the solute. It is unfortunate that the existence of the indirect interaction often receives short shrift (for example, popular “docking” computer programs and undergraduate biochemistry curricula that focus on the existence of direct interactions only).
Indirect solvent-mediated interactions are often more important than specific solute-target interactions. It is well-known that general anesthetics, sedative-hypnotics, and heart-muscle-depressant drugs display no structure-activity relationship and that cyanuric acid and urea act as therapeutic drugs for sickle cell anemia through indirect solvent interactions and not by direct interactions with the protein itself. Furthermore, even when the solute-target interaction is known to be of a direct or indirect origin, the mechanism is still uncertain because the solvent medium often consists of multiple components.
For example, with regard to the indirect mechanism of action of general anesthetics, Linus Pauling suggested that gaseous anesthetics react with water near the surfaces of nerve membranes in the form of microcrystalline hydrates. Fluorinated compounds such as CF4 and SF6, which only form hydrates with difficulty at body temperature, were then used to test whether the actual site for anesthetic action was an aqueous or lipid environment. Although the results were somewhat tilted in favor of the nonaqueous mechanism, additional experiments seem to be required to conclusively settle the question.
The work of Arieh Ben-Naim of the Hebrew University of Jerusalem focuses on many of the preceding problems. Drug mechanisms are molecular phenomena and therefore demand molecular physical interpretations (i.e., statistical mechanics). Because most biochemists and pharmaceutical chemists have not had the opportunity to develop a sound foundation in statistical mechanics, many potential difficulties go unnoticed, and consequently, experimental results are open to interpretation.
Ben-Naim’s textbook “Statistical Thermodynamics for Chemists and Biochemists” remedies this problem as well as proposes concrete methods to distill and quantitate solute-solvent-target interactions by an inversion of the Kirkwood-Buff theory of solutions. The methods may be implemented technically with positive utility by experimental experts. Hence, the honest response by Robert Raffa of Temple University that “We don’t know how it works,” may perhaps be altered to an equally honest but satisfying, “We know how it works.”
John Raymond Stanks
As a longtime user of acetaminophen, I enjoyed reading the interesting article by Carmen Drahl. Robert Raffa’s statement in the final paragraph seems to indicate the need for a specific symposium on the drug. This symposium, involving the relevant researchers, could, conceivably, “put it all together.”
Richard D. Stacy