Drug side effects are often due to unintended interactions with our body besides the target site. Modern drugs are becoming more specific for their targets, thanks to the tremendous research efforts in reducing side effects. However, on-target drug actions may still produce side effects, sometimes severe adverse ones. Opioid painkillers, for instance, caused over 70,000 deaths in the US in 2019. In Europe, a “silent opioid epidemic” is also raising concerns. This is because opioids act on our opioid receptors, which control not only pain, but also reward, addiction, mood and other functions. Like most (if not all) drug targets, opioid receptors are nanosized multifunctional molecular devices. Where is the right button for painkilling?

Dr. Sebastien Granier and his team in the IGF just made a big step toward the answer. Opioid receptors are G protein-coupled receptors (GPCRS). GPCRs are proteins on the cell surface that regulate cellular responses to extracellular stimuli. Humans have 800 types of GPCRs, which contain the targets of ~40% of marketed drugs. Most of them have similar shapes and two main output “ports” (signaling pathways) toward the interior of cells. Driven by the stimuli (e.g. drug molecules), a GPCR can change to different conformations, which open/close the ports in specific ways to trigger different cellular responses and body reactions. How to design drugs that Nature has given us such delicate devices, however, without the manual books.

In 2012, Dr. Granier and his colleagues obtained the first high-resolution 3D structures of opioid receptors. In 2015, his team developed a strategy to probe the conformational changes in the µ-opioid receptor during its response to opioid painkillers. This year, the team has just discovered how different opioid painkillers open/close the two ports of the receptor separately (and trigger different cellular responses), by pressing a sweet spot in the receptor’s heart. This work, published in the Molecular Cell journal, combined computer simulations (~2 months of calculations on one of France’s fastest supercomputers, OCCIGEN), NMR spectroscopy and live-cell pharmacology assays. It describes the mechanism of this nanodevice in atomistic detail. To see a 3D presentation, click here. The team is now investigating whether the mechanism is universal for other GPCRs. Future drugs will be more and more precise, as we understand better and better their targets.

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