Rethinking How Medicines Work
Why timing may matter as much as dose
Dr. Asawari Pagare, Bioinformatician, UW Medicine
When we think about medicines, we often focus on how much of a drug is required to reach a therapeutic effect. But living systems respond not only to quantity, but they also respond to timing. This article explores how patterns of exposure shape biological responses and why time may be an overlooked dimension in drug development.
BODY
A visit to the doctor’s office often begins with routine questions. Age, weight, blood pressure, current medications, and medical history are all taken note of. These questions may appear simple, but they are central to determining the dosage of a medicine someone might be prescribed.
That small number in milligrams printed on a prescription represents years – often decades of scientific work. Countless molecules were tested before one survived. Endless data were reviewed before that amount was declared both safe and effective. 08045845678
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Fig.1. (a) The drug discovery and development pipeline requires years before a drug reaches clinical practice. It begins with understanding the disease biology, identifying a target, discovering a molecule that engages with the target and is safe followed by multiple phases of trials to determine the right amount. (b) Drug targets are protein molecules that are dynamic in nature, and they function not only on structural information but also temporal information. They experience environment that is much noisier than what blood samples capture. (c) Expanding drug development to include time as an important variable may help control the responsiveness of targets without worrying about adaptation and withdrawal.
From drug discovery to development
Drug discovery follows in hierarchy. It begins with understanding disease at its most basic level, through biology. Our bodies function through constant communication. Molecules send signals to one another, triggering responses in a relay like system. In a healthy state, these signals stay balanced. But if one part of the pathway becomes too active, not active enough, or overly sensitive, the system is disturbed. That disturbance is what we recognise as disease.
The imbalance in disease helps scientists identify a target, the part of the signaling system where a drug must act to restore the balance. Once a target is identified, chemists begin searching for molecules that can attach to it and adjust its behavior to restore the balance. Years are spent refining those molecules, so they remain stable, selective, and able to survive inside the body. Thousands of molecules fail here. A molecule must travel through very different environments before reaching its destination, the acidic through basic conditions of the gut, the enzymes of the liver, and the immune surveillance of the bloodstream. It must survive each of these checkpoints before it can finally reach the place where it is meant to act.
A molecule that survives this scrutiny is then considered a hit, and the next set of researchers start exploring two fundamental questions: What the body does to the molecule, and what the molecule does to the body.
This is where a shift in perspective may be necessary.
Targets are dynamic
We often talk about what the body does to a drug as if the body were simply a container that absorbs, distributes, and eventually eliminates it. And we talk about what the drug does to the body as if its target were fixed, like a lock waiting for a key. If targets responded only to the presence of a molecule, the story would be simple. The more molecules present, the stronger the response. Once all receptors were occupied the response would level off. Dose would explain everything. For a long time, this framework worked well. It allowed scientists to measure drug action, draw curves, and compare potency and safety. It helped make pharmacology quantitative. But targets are not simple switches.
Targets do not operate by merely turning on and off. Living systems rarely rely on such limited information. Biologists are increasingly discovering that targets are far more flexible than that. Many medicinal targets are receptors, proteins that sit on the surface of cells. They are embedded in the cell membrane and cannot move elsewhere to carry a molecule. Instead, they detect its presence and pass information into the cell. In other words, targets act as interpreters. And interpretation is rarely static. A receptor can exist in several slightly different shapes. These small structural differences influence how the receptor communicates with the inside of the cell. The same drug molecule can stabilize different shapes of the same receptor, and those shapes can favor different signals. A brief interaction may trigger one type of response. A longer interaction may gradually shift the receptor into another functional state.
Counting how many molecules are present at a moment is only part of the information that the receptors are sensing, and this becomes limiting in the scientific analysis. If we measured drug concentration in the blood at that moment, the numbers might look identical. But if one receptor has been exposed continuously for weeks while another has encountered the drug only occasionally, their behavior may not be the same. Binding, then, is not the end of the story in a drug’s interaction with the body. It is the beginning of a process of interpretation at the molecular level before the body produces a larger, visible response. Sensitivity, on the other hand, reflects how that target processes information over time.
From a receptor’s point of view
We measure drug concentration in the blood because blood is easy to sample. These measurements give us curves with peaks and troughs. From them we calculate half-lives and overall exposure. But the actual target of a drug often lives inside tissues, not necessarily in the bloodstream. The concentration around that target may rise and fall in ways that blood measurements cannot fully capture. From the receptor’s point of view, exposure may not look like the smooth curve scientists draw from blood samples. Instead, the receptor experiences a constantly changing environment -- small rises and falls in concentration, molecules attaching and detaching, signals turning on and gradually settling down. This is where physics enters the picture.
At the molecular level, nothing is perfectly steady. Proteins shift shape. Chemical bonds form and break. Signals move through the cell in short bursts. These events are dynamic processes. A receptor does not remain in one fixed shape while waiting for a drug molecule. It naturally shifts between several possible shapes. When a drug binds, it gently nudges the receptor toward one of those shapes. If a new exposure arrives before the system has completely relaxed from the previous one, the receptor does not encounter it as something entirely new. Its physical state has not fully reset. Some shapes persist for a while. Some signaling partners remain engaged. Feedback loops inside the cell may still be active. The next exposure is interpreted in light of the previous one. So, timing matters. The more I think about signaling systems, the less comfortable I am treating drug targets as fixed points of interaction. They are adaptive. The receptors remember what they experienced in the recent past. This is not memory in the way we think of memory in the brain. Molecular memory is much simpler. It comes from physical states that take time to settle and signaling processes that take time to quiet down.
Fluctuations, therefore, are not noise. They carry information.
Redefining efficacy
Current drug-development strategies assume that maintaining a certain concentration of a medicine will maintain a certain effect. Expanding this view could lead us toward dosing strategies that preserve the sensitivity of targets and the quality of signaling over time. Dose frequency is already considered in prescription. But it is often chosen mainly to maintain stable drug levels in the bloodstream while keeping the average exposure safe.
Dose remains essential because safety depends on it. What may need to expand is how we define efficacy. Dose is not only about staying within a safe window and avoiding toxicity. It is also about interacting intelligently with the machinery inside living cells using timing and pattern in ways that allow targets to operate at their best responsiveness while still remaining safe. This balance is not yet fully considered in how drugs are developed. One reason may be the communication gap between scientific disciplines. Currently, physics and biology simply describe the same reality in different languages. Somewhere between complex biology and meaningful physical equations must lie a sweet spot that will give us more control over the machinery inside living systems.
A stronger effort to translate ideas across disciplines beyond jargon and beyond biases could expand how we design drugs. Like any new direction, this is easier said than done. It is difficult to measure drug concentrations at the exact site where a drug acts. It is even harder to map every possible structural state of a receptor and understand how each behaves. Each of these fields is advancing rapidly, and their integration may come sooner than we expect.
But before complex integration comes a simpler shift in thinking.
Instead of asking only how much drug is needed to produce an effect, we might begin asking how the target experiences that exposure over time. Is it constantly pressed? Is it given time to recover?
Is it nudged repeatedly in small intervals? Does the pattern support stability, or does it gradually push the system toward adaptation? This shift simply requires reframing the question. The goal is not only to maintain concentration but also preserve responsiveness. Rather than seeing adaptation, tolerance, or withdrawal as unexpected late-stage complications, we might recognise them as predictable outcomes of how biological systems process long-lasting signals. A receptor that is continuously stimulated will recalibrate. A pathway that is constantly activated will reorganise. These are natural properties of dynamic systems.
The milligram number printed on a prescription captures only one dimension of the interaction between a drug and its target. Time is another part of the signal, and it is often overlooked.
As we continue refining how drugs work, recognising time as a biological variable may help us design treatments that act not only effectively, but also in harmony with the adaptive nature of living systems.
The principle is simple: living systems encode information in time.
References:
- Berdigaliyev, Nurken, and Mohamad Aljofan. "An overview of drug discovery and development." Future medicinal chemistry12.10 (2020): 939-947.
- Copeland, Robert A. "The dynamics of drug-target interactions: drug-target residence time and its impact on efficacy and safety." Expert opinion on drug discovery 5.4 (2010): 305-310.
- Shahrezaei, Vahid, and Peter S. Swain. "The stochastic nature of biochemical networks." Current opinion in biotechnology19.4 (2008): 369-374.
- Pagare, Asawari, and Zhiyue Lu. "Mpemba-like sensory withdrawal effect." PRX Life 2.4 (2024): 043019.
Dr. Asawari Pagare is a bioinformatician at UW Medicine where she studies the genomics of myositis, an autoimmune disease that is not yet well understood. She earned her PhD in Chemistry from the University of North Carolina at Chapel Hill, USA, where she explored how timing and fluctuations influence how living systems interpret signals relevant to medicine.
