Do you know people who swear by Tylenol as a pain reliever and other people who say it doesn’t work for them at all? One of the unsolved mysteries in chemistry is a clear explanation for why medicines work differently in different people. The chemistry of drug development can seem straightforward on the surface. There are receptors on the surface of human cells that respond to signals from things like hormones and drugs and determine how the body reacts. Drug makers create medicines that target these receptors in an effort to treat illness. Although drug makers design drugs that bind tightly to certain receptors, the drugs are not always as effective as expected, and the effectiveness can vary among patients. Research reported in a recent ScienceNewsToday article (based on an ACS Medicinal Chemistry Letters paper) provides a possible explanation for why.
A team of scientists in Japan studied the histamine H1 receptor, which is involved in allergic reactions, inflammation, and other functions in the body, and how two isomers of a compound called doxepin bind to this receptor. Researchers found that the z isomer bound to the receptor with much higher affinity than the e isomer and that a single amino acid, Thr1123.37, was responsible for the difference. They then created a mutant receptor and studied how each isomer reacted with each receptor. In particular they measured the binding energy and the balance of two thermodynamic forces, enthalpy and entropy, in the binding process. Enthalpy describes how strongly molecules stick together and entropy describes how much freedom they have to move. The researchers discovered that small differences in compounds, such as the difference in a single amino acid, can change the balance of the enthalpy and entropy forces in the bond which can dramatically impact the tightness of the bond.
Differences in binding energy for two different isomers of doxepin
This research may help explain why some drugs work better than others, even when they look very similar. Understanding the impact of the entropy and enthalpy balance on binding can help drug makers design drugs that are even more selective for the target. This article has the potential to reduce chemophobia because it reminds readers that chemistry is essential to maintaining human health. It shows scientists using their knowledge to help people in their everyday lives.
Primary Source:
ScienceNewsToday, Editors of. “This Tiny Molecular Sentinel inside Your Cells Decides How Your Body Heals.” Science News Today, 15 Feb. 2026, www.sciencenewstoday.org/this-tiny-molecular-sentinel-inside-your-cells-decides-how-your-body-heals.
Secondary Source:
Kaneko, Hiroto, et al. “Enthalpy–entropy trade-off underlies geometric isomer selectivity in histamine H1 receptor–doxepin interaction.” ACS Medicinal Chemistry Letters, vol. 17, no. 2, 27 Jan. 2026, pp. 490–494, https://doi.org/10.1021/acsmedchemlett.5c00696.
