What is it about?

We have all experienced the long list of side effects when listening to an advertisement for the latest and greatest medicine. Why are there so many side effects, and why does a medicine do so many things to the body that are not related to the disease being treated? Part of the answer lies in our body's metabolism system. Understanding how a medicine is metabolized within a person is a vital part of the drug development process. Decades of research have generated a wealth of knowledge on metabolic pathways in the body, but new drugs continue to cause a variety of side effects. Why? First, any given drug can interact with a vast diversity of systems in the body, although the drug was not intended to interact with those systems. Second, our detoxification programs are tuned to respond to a vast diversity of chemical exposures. The metabolism of a drug is complex and impossible to predict. Pregnane X receptor (PXR) is a protein that detects chemicals and activates a drug metabolism program. PXR and its program are responsible for the majority of known drug metabolism events, and much effort is placed in avoiding PXR activation. However, PXR has evolved to detect a wide variety of chemicals, so a set of rules for circumventing PXR activation is difficult to achieve. To address this problem, in our study, we have described a method that can be applied to reduce or avoid PXR activation by drugs. Through a combination of chemistry, biochemistry, cell biology, and structural biology, we found that our method can be applied to multiple medicinal compounds. The information can be integrated into drug development pipelines to more efficiently generate medicines with more favorable metabolism profiles.

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Why is it important?

One of the most important safety features in the human body is detoxification. Because of its role in removing potentially harmful substances from a person, the detoxification system detects a large variety of chemicals, including pharmaceutical drugs, and metabolizes them. This is beneficial for preventing chemical harm to a person but prevents medicines from performing their proper function. These metabolism events lead to side effects, causing discomfort or more serious problems during a person's drug regimen. In our study, we have characterized a component of the detoxification system and described a method to prevent metabolism through the component. This knowledge can be used to create safer, more effective drugs in the future.

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This page is a summary of: Structure-guided approach to modulate small molecule binding to a promiscuous ligand-activated protein, Proceedings of the National Academy of Sciences, February 2023, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2217804120.
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