New Delhi, Jun 10 (PTI) Fundamental conditions of human biology, such as body temperature and calcium levels in cells, may influence how drugs interact with a target, sometimes even flipping the drug’s effect entirely, according to a new study.
Findings published in the journal Nature Structural and Molecular Biology could help explain why drug candidates can look promising in early lab tests but fail later in development.
Researchers from the US’ Northwestern University found that a drug, once dismissed as ineffective, suddenly worked when it was tested under more realistic conditions mimicking the human body.
“Here we show two such factors — temperature and Ca2+ — remodel the function and pharmacology of TRPM4, an ion channel implicated in cardiac conduction, immune regulation, cancer and intestinal-fluid homeostasis,” the authors wrote.
They added that the study could point towards a smarter way to design more effective medicines with fewer unwanted side effects.
“Drugs don’t act in isolation. They act within the physiological environment of the cell. By incorporating temperature and calcium into our experiments, we uncovered drug activities that were completely invisible before,” co-lead researcher Wei Lü, professor of molecular biosciences, said.
In early evaluations, scientists commonly test drugs in simplified laboratory conditions — often at room temperature and in artificial chemical environments that may not necessarily reflect the realities inside the human body.
However, proteins are dynamic, shape-shifting molecules whose structure can change in response to surroundings, including temperature and chemical signals like calcium, the researchers said.
Drugs often work by binding to proteins, and therefore, even small structural shifts in a protein can dramatically change a drug’s ability to work. In other words, if the protein changes its shape, the drug’s effectiveness can change too, they said.
For the study, the researchers looked at ‘TRPM4’, a protein channel involved in heart rhythm, immune responses, among other essential biological functions. They test triphenylphosphine oxide (TPPO), a small synthetic molecule, on cells expressing the TRPM4 channel.
In lab tests under simplified conditions, TPPO appeared inactive, showing no effect on TRPM4.
However, testing the molecule at body temperature (37 degrees Celsius or 98.6 degrees Fahrenheit) and with realistic calcium levels, the previously inactive compound was found to powerfully activate the TRPM4 channel.
“This completely overturned what we thought we knew. It shows that we may be overlooking important drug candidates simply because we are not testing them under the right conditions,” co-lead researcher Juan Du, professor of molecular biosciences, said.
In another set of experiments, the team tested a compound called Necrocide-1, known to activate TRPM4. At low calcium levels, Necrocide-1 behaved as expected, switching the protein channel on.
However, when calcium levels increased — as they often do when cells are stressed, injured or diseased — the Necrocide-1 molecule largely lost its effect, the researchers said.
Simply put, the cell’s internal environment determined whether the drug worked, they added.
To understand why this happens, the researchers used cryo-electron microscopy, an imaging technique that can visualise proteins at near-atomic resolution.
The TRPM4 protein channel was found to contain a flexible drug-binding region that changes shape depending on temperature and calcium levels — the shape shifts determine which compounds can bind to the protein and what happens when they do.
“These structures show exactly how the environment reshapes the binding pocket. Even small changes in temperature or calcium can shift how a drug interacts with the protein,” Du said.
