"One medicine cures many diseases" is no longer a legend? "Panacea" may become a reality!

□ Feng Yan, Science Times reporter Wang Chun

How wonderful it would be if one pill could cure several diseases. This dream may really come true. Wang Sheng's research group at the Center for Excellence in Molecular Cell Science of the Chinese Academy of Sciences proposed a new method for designing multi-target and multi-functional drugs, providing new ideas for the development of drugs for complex mental illnesses. The research results were published in the internationally renowned academic journal Cell on March 28.

The traditional pharmaceutical paradigm focuses on selectivity to avoid side effects, and usually adopts the strategy of "one molecule, one target, one disease". However, for some complex multifactorial diseases, such as mania and depression manifested by mental illness, and bipolar disorder, one drug often cannot cover several symptoms, so it is crucial to develop a drug that can act on multiple targets at the same time. How to design such a multi-target, multi-functional drug has always been a major problem in the scientific community.

Remdesivir coronavirus drug and target (copyright image of the gallery, reprinting and use may cause copyright disputes)

In the view of researcher Wang Sheng, the relationship between drugs and targets is like that between keys and locks. If a new molecule that is as variable as Kun diving into the seabed and Peng flying in the sky can be designed, when encountering different lock cores, it can bind to different receptor targets in different forms and regulate receptor activity, thus alleviating various symptoms of the disease at the same time. Inspired by this, Wang Sheng's research group challenged this "master key" and identified two different "lock cores". Based on years of research on receptor structural pharmacology, Wang Sheng's research group found that agonist ligands of the serotonin receptor family tend to adopt a "stretched upward" binding state, while antagonist ligands tend to adopt a "bent downward" binding state. In other words, as long as a variable "key" that can both "stretch upward" and "bend downward" can be designed, these two "locks" can be opened at the same time.

Wang Sheng's research group figured out the various shapes of the "holes", and then turned to computational biologists to use programs to find a chemical "skeleton" that can both deform and connect the two drug structures at the same time. Serotonin is a widely studied neurotransmitter that affects almost every aspect of brain activity. Based on the serotonin 1A receptor and serotonin 2A receptor, there are 2.2 million candidate compounds, which were repeatedly screened with different criteria. More than 240,000 were selected, 4,537 were selected from the 240,000, 296 were selected from the 4,537, 10 were selected from the 296, 2 were selected from the 10, and 1 was selected from the 2.

Wang Sheng's research group designed a representative multi-target molecule IHCH-7179 based on serotonin 1A receptor and 2A receptor. When binding to serotonin 2A receptor, IHCH-7179 "bends downward" and dives into the deep pocket, inhibiting the activity of this type of receptor, thereby suppressing the mania and hallucination symptoms of mental patients. On the contrary, when binding to serotonin 1A receptor, IHCH-7179 "stretches upward" and activates this type of receptor, thereby improving the cognitive function of mental patients.

This "one in 2.2 million" compound IHCH-7179 really lived up to expectations. Using a variety of preclinical animal models simulating schizophrenia and dementia, Wang Sheng's research group found that it can antagonize serotonin 2A receptors and inhibit the symptoms of psychosis in mice, and activate serotonin 1A receptors to improve the cognitive function of schizophrenia and dementia mice, supporting the multi-functional activity and potential clinical application value of multi-target molecules.

Xu Huaqiang, co-corresponding author of the paper and researcher at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, said that this is the first time in the world that central nervous system drugs have been designed clearly based on targets, and it is also a direction for the future development of structural biology.

Wang Sheng revealed that a multi-target drug for the treatment of schizophrenia designed using this method is currently being developed in cooperation with Shanghai Pharmaceuticals and is expected to enter clinical trials in the second half of the year. It will be combined with more effective targets to turn it into a controllable molecule.