On March 28th, researchers including Dr. Sheng Wang from the Molecular Cell Science Excellence Innovation Center of the Chinese Academy of Sciences, Dr. Jianjun Cheng from the iHuman Institute at ShanghaiTech University, and Dr. Huaqiang Xu from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, collaborated to propose a novel method for designing multi-target, multi-effect drugs. This method, based on Flexible Skeleton Chemical Informatics (FSCA), opens up a new avenue for drug development targeting complex psychiatric disorders. The related research findings were published online in Cell.
Hunting for the "Master Key" to Treat Mental Disorders
Similar to how a key can only unlock one lock, traditional drugs are typically developed following the concept of "one molecule, one target, treating one disease" to minimize side effects.
However, in the field of central nervous system disease treatment, due to the complexity of disease mechanisms and the diverse range of symptoms, traditional single-target drugs fall short of meeting patients' needs. For the treatment of complex psychiatric disorders, it is crucial to develop drugs that can simultaneously act on multiple targets.
Taking serotonin 2A and 1A receptors as examples, these two receptors are primary targets for many psychiatric drugs. Serotonin 2A receptor inhibitors have shown significant clinical efficacy in alleviating psychotic symptoms associated with schizophrenia, Alzheimer's disease, and Parkinson's disease-related psychiatric disorders, but they fail to slow down cognitive decline in patients. On the other hand, serotonin 1A receptor agonists can improve psychiatric symptoms in patients with Alzheimer's disease. In the treatment of schizophrenia, the combined use of both types of drugs can simultaneously improve psychiatric symptoms and some cognitive functions.
In previous studies, Dr. Wang's team identified a drug that effectively alleviates symptoms of schizophrenia without accelerating cognitive decline. Building upon this discovery, the team attempted to design a new strategy to obtain a "master key" targeting different receptor molecules.
Simply combining different compounds at once is not feasible. On one hand, the targets of psychiatric drugs are often located inside receptors, with a very limited space for drug molecule binding, rendering a "big key" composed of multiple compounds unable to unlock the lock. On the other hand, different drug molecules often interact with each other, causing unforeseen side effects.
The research team integrated multidisciplinary technical approaches such as chemical informatics, structural biology, cell functional studies, and behavioral pharmacology to identify the universal flexible skeleton required for designing multi-target drugs and proposed a novel concept for designing multi-target, multi-effect drugs - FSCA.
Dr. Wang pointed out, "Thanks to the breakthroughs and developments in structural biology in recent years, we can know a lot about targets and the structure of receptor binding sites, thereby targeting compounds we want specifically."
"Just as the Kun fish swims in the northern darkness and transforms into a Peng bird soaring in the sky," similar to how the Kun and Peng change forms, multi-target drug molecules designed based on flexible skeletons can also, like Kun and Peng, interact with different receptor targets in different forms or positions to regulate receptor activity, thereby effectively alleviating various symptoms of psychiatric disorders.
How to Design the Next Generation of Multi-Target Drugs?
Looking back on the history of drug discovery, many early drugs were obtained by chance or through modifications to the structure of existing molecules, gradually advancing into clinical use. "The main purpose of this work is to answer how to design the next generation of multi-target drugs," Dr. Wang pointed out. Life sciences and drug design ultimately return to universal principles. The basic idea of this work is not complex - it is about finding flexible skeletons to allow the key itself to be variable, thereby designing multi-target compounds.
The research team screened 10 molecular skeletons from a vast compound library and found that seven of them could achieve "dynamic adjustability." Based on one of these skeleton structures, the team designed a representative multi-target molecule IHCH-7179 using the FSCA method, with serotonin 1A and 2A receptors as blueprints.
The FSCA Design Concept: Insights from "Cell" Magazine
Recent cryo-EM structural analyses have confirmed that when binding to the serotonin 2A receptor, IHCH-7179 adopts a "bent-down" conformation, penetrating deep into the pocket, thereby inhibiting the activity of this type of receptor, thereby suppressing manic and hallucinatory symptoms in psychiatric patients. However, when binding to the serotonin 1A receptor, IHCH-7179 adopts an "extended-up" conformation.
Furthermore, researchers conducted experiments in various preclinical animal models simulating schizophrenia and dementia, and found that IHCH-7179 suppresses psychotic symptoms in mice by antagonizing the serotonin 2A receptor, and improves cognitive function in schizophrenic and demented mice by activating the serotonin 1A receptor. These results suggest that IHCH-7179 has the potential for the treatment of various central nervous system disorders and may become a novel drug with multiple targets and effects.
According to reports, a new drug designed by the Wang Sheng team using this method is expected to enter clinical trials this year.
Xu Huaqiang, another corresponding author of the article, pointed out: "Medical research is a systematic endeavor. This work proposes a new concept, which is to design drugs for the central nervous system based on targeted receptors. For drug development, this is a new beginning and can be applied to more neurotransmitter receptors and even other disease treatments in the future."
For more information, refer to the related paper: https://doi.org/10.1016/j.cell.2024.02.034
