Scientists at St. Jude Children’s Research Hospital have demonstrated how drug makers can avoid two key problems: toxicity and resistance.
The researchers made slight changes to a small molecule to reduce its metabolism and elimination by the cellular detoxification network regulated by the pregnane X receptor (PXR). This research provides a framework to develop solutions to the long-standing issue of how to evade detoxification networks using medicinal chemistry. The findings were published in Proceedings of the National Academy of Sciences.
The researchers were able to change a drug that normally binds well to the detoxification receptor PXR into a drug that bound poorly. The altered drug stretched out the binding region of PXR, making binding energetically unfavorable. Structural modification of the drug lowered the levels of PXR-induced enzymes – indicating this approach could be used to evade detection of a drug by the detoxification network in drug development. The potential implications of the research are vast, because many drugs interact with PXR, and over half of all clinically approved drugs in the U.S. are metabolized by the PXR-induced enzymes.
