Poison turns into medicine! How did scientists find a cure that “doesn’t exist” in reality?

▎WuXi AppTec Content Team Editor

When it comes to psychedelics, is everyone’s first impression of it relatively negative? Indeed, its hallucinogenic, potentially addictive, effects are staggering. But in reality, psychedelics were originally developed to treat mental illness, and some research has yielded preliminary results. It was only later that psychedelics were banned from use in any setting due to its overuse for recreational use due to its pleasing properties. Medicine is good medicine, but human beings “played it badly”.

It wasn’t until nearly a decade ago that psychedelics were released from the “little dark room” and could continue to be studied for their use in the treatment of disease. Today our story will begin with the indissoluble bond between psychedelics and the treatment of depression.

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The “psychedelic drug” derived from magic mushrooms – a double-edged sword for depression

As early as 2016, scientists from the United States proposed that a hallucinogenic compound extracted from magic mushrooms may be used to treat patients with major depression. Researchers have observed that ingesting large doses of this mushroom can change a person’s personality, making him lively and cheerful, and this effect lasts for an extremely long time, even for more than a year.

If the joy-enhancing ingredients in this mushroom can be successfully extracted to treat depression, what a drug it could be! You know, the conventional antidepressant drugs currently on the market are only effective for about 1/3 of patients, and in addition to having to be taken every day, it usually takes several weeks to become effective.

As soon as they say it, researchers have actually extracted psilocybin, the main ingredient in “magic mushrooms,” and set out to develop it as a treatment for Medications for treating depression. In early clinical trials, psilocybin showed excellent antidepressant performance—as was previously observed, patients experienced good results after taking the drug a few times, and the effects were lasting a year or more. Based on this, psilocybin was granted breakthrough therapy designation by the FDA in 2018.

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However, the origin of psilocybin as a “psychedelic drug” has cast a shadow over its clinical course. If the hallucinogenic side effects of “psychedelic drugs” such as psilocybin cannot be resolved, even if they can be approved for marketing in the future, there are many limitations in clinical practice. First of all, when using psychedelic drugs, patients must be under the supervision of medical staff for a long time, otherwise the hallucinations caused by psychedelic drugs may cause unexpected accidents. Second, psychedelics can induce psychotic-like disorders, so psychedelics are also not recommended for patients with first-degree relatives (parents, children, and siblings) who suffer from schizophrenia.

Overall, the cost and complexity of using these drugs is simply too high, because clinics and health care providers will never be able to get enough of them based on the sheer number of people with depression today. So is there a way to separate the antidepressant and hallucinogenic effects of “psychedelics”?

Yes! Since 2020, many different research groups have demonstrated that it is possible to separate the “effects” from the “side effects” of psychedelics. Some researchers have found that the antidepressant effect of psilocybin comes from binding to the serotonin 2A receptor, which can prompt the body to secrete a “happy molecule” in large quantities, while its hallucinogenic effect is due to the activation of serotonin A downstream signaling pathway of the 2A receptor, regulated by lipids. Researchers can design drug molecules that prefer the antidepressant pathway, so that psychedelic drugs have only “effects” and not “side effects”. This provides a theoretical feasibility for developing non-psychedelic psychedelic drugs to treat depression.

Computer drug development technology makes theoretical ‘virtual medicine’ a reality

In fact, the scientists who discovered the new drugs we’re introducing today didn’t start out looking for antidepressants, they just wanted to find molecules that affect the brain’s serotonin system, which is involved in regulating mood . As the research progressed, the researchers became interested in research in this area after the team learned that other groups had found psilocybin to have a “miraculous” effect on depression.

At the time, the research team was full of talented people. Brian Shoichet, a scientist at the University of California, San Francisco, has pioneered the use of computer simulations for drug development. And Jon Ellman, a chemist at Yale University who is well-versed in chemical molecular structures, has also developed the core method for synthesizing the structure of another common psychedelic drug, LSD. With Chochet, they built a compound library of 75 million 3D structures of molecules using basic molecular infrastructure that could be easily replicated from other labs. Most of these molecules are computer “fictitious” compounds that may or may not exist in reality.

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During a conference discussion, Chauchette and Ellman had an interesting idea—whether a phantom like psilocybin could be found in their virtual library of molecules Molecules that work in the same way as phantom drugs, leading to better psychiatric drugs for depression or anxiety? And they hope the drug won’t produce its hallmark side effect — hallucinations.

Now, there is a virtual molecular library, everything is ready, only one “east wind” is owed. Since psychedelic drugs work by interacting with receptors for serotonin 2A, the two immediately found an expert in the field to join the team.

Bryan Roth is a psychiatrist and pharmacology researcher at the University of North Carolina at Chapel Hill who has worked on the structural biology of the neurotransmitter serotonin and its receptors Published groundbreaking research. As a result, the three brought their expertise in the professional field to the extreme and jointly led this interesting project.

After refining screening methods and targets, researchers began with millions of drug candidates. But when they used a computer to match the 3D structure of these drug candidates with the 3D structure of the serotonin 2A receptor — like a 3D jigsaw puzzle, only 17 of the millions of drug candidates were left. Potentially available molecules. After the researchers actually synthesized the 17 candidate molecules, only two candidate molecules remained that could interact with the serotonin receptor. Fortunately, both molecules were successfully validated in mice, and their findings were recently published in the journal Nature.

In one experiment, researchers tested whether these candidate molecules worked by placing mice under stress by hanging them upside down for a few minutes. Mice without depressive symptoms struggled to break free, while mice bred to exhibit depressive symptoms did not. But when the depressed mice were treated with computer-generated molecules, they struggled when they were hanged upside down. In addition, the mice did not show the behavior of shaking their heads or twitching their noses, as the mice that had hallucinated after receiving the psychedelic drug.

That said, these molecules do have antidepressant activity and are not yet hallucinogenic. Even more surprising, they were as effective in mice as the existing drugs for depression, fluoxetine or Prozac, but at 40 times lower doses! In addition, the antidepressant effects of the silicon-derived molecule persisted for weeks, despite the small doses.

Professor Chauchette proudly stated in the interview: “The physical properties of these two candidate molecules are particularly good, the brain penetration is high, and they are also the most effective. Another advantage of these new therapies is Yes the antidepressant effect occurs within hours of taking the drug and can last for a year or more.

Some neuroscientists have also expressed high praise for the research, which suggests that psychedelic-based drugs could bring depression patients closer to a cure than simply treating the symptoms of the disease.

Currently, researchers have moved from using computer-based methods to screen drug candidates to the general stage of drug discovery. While the findings are encouraging, the efficacy is still nowhere near what the researchers wanted. Therefore, the team made small modifications to the structures of these candidate molecules to ensure that they better fit the serotonin 2A receptor, while removing unnecessary moieties that could contribute to off-target effects or toxicity. For them, there is still a long way to go before the drug actually enters the clinic.

Research Highlights – Planting “Melons” and Getting “Beans”

Professor Chauchette said in an interview: “Although this computer simulation method has a lot of false negatives – it’s like throwing a net and trying to catch a lot of broken shoes. , but it is correct enough.”

What was most surprising about this study was that while the potential drug targets initially hoped to be discovered were psychedelics with structures similar to LSD, the The structure of the potential drug molecule that was eventually discovered did not resemble LSD at all. This seems to be a little joke between God and the researchers. But on the other hand, this model of potential drug screening through computer simulations expands the boundaries of existing drug development models, potentially allowing more “unimaginable” new drug molecules to be discovered.

The significance of this research is not only the first successful use of computer technology to virtually conceive a drug capable of separating antidepressant and hallucinogenic effects, but also to demonstrate that the Feasibility of large-scale computational strategies for drug development. Perhaps in the near future, biopharmaceutical companies will have the opportunity to use this drug development method to diversify the drug development model and have more possibilities, so as to develop better drugs and ultimately benefit more patients. .