Scientists reveal key molecular mechanisms of rapid antidepressant drugs

A few days ago, the Zhu Shujia research group of the Chinese Academy of Sciences Brain Science and Intelligent Technology Excellence Innovation Center (Institute of Neuroscience) and the Luo Cheng research group of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences have revealed the key molecular mechanism of rapid antidepressant drugs, targeting NMDA receptors The research and development of designing new antidepressants provides an important basis
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On July 28, Nature published the results of this research online

Depression is one of the most common mental illnesses
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Ketamine, as a new type of antidepressant with rapid onset, is the most important discovery in the field of antidepressants in recent decades

In this study, Zhu Shujia’s team focused on the two most abundantly expressed subtypes of GluN1-GluN2A and GluN1-GluN2B NMDA receptors in the adult mammalian brain.
The eukaryotic expression system was used to perform a large number of protein expression and purification in the early stage.
Conditions groping
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After obtaining a stable NMDA receptor protein, the researchers combined with cryo-electron microscopy technology to analyze the three-dimensional structure of ketamine-bound human GluN1-GluN2A and GluN1-GluN2B subtypes of NMDA receptors

"Our team identified GluN1-N616 and GluN2A-L642 (homologous GluN2B-L643) through point mutation screening and electrophysiological experiments as key amino acids involved in ketamine binding
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Mutations at these two sites will have a significant impact The effectiveness of ketamine in inhibiting NMDA receptor channel activity strongly proves that these two key amino acids play an important role in the process of ketamine inhibiting channel activity

In order to further analyze the interaction between the receptor and ketamine, Luo Cheng's research group conducted molecular dynamics simulations
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Luo Cheng, the co-corresponding author of the paper, told the Chinese Journal of Science: "The simulation results show that GluN2A-L642 contributes the most to the binding energy of ketamine, and its hydrophobic side chain can form a hydrophobic interaction with ketamine.

The study "sees" and confirms the binding site of ketamine on the NMDA receptor through electron microscopy, and reveals the hydrogen bonding effect of GluN1-N616 and the hydrophobic effect of GluN2A-L642, which stabilizes the channel where ketamine binds to the NMDA receptor It plays a key role in the process of blocking the passage in the cavity

Pu Muming, academician of the Chinese Academy of Sciences, said that this series of discoveries revealed the molecular mechanism of rapid antidepressant drugs targeting glutamatergic receptors, and provided important information for the design of new antidepressant drugs and personalized precision medicine
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Zhang Mingjie, an academician of the Chinese Academy of Sciences, also spoke highly of this: the study gave a very direct mechanism of how ketamine interacts with key amino acids in ion channels, and provided how to design new compounds through this structural information, and make these compounds It can achieve more selective and effective inhibition of the activity of NMDA receptors, and at the same time can reduce the side effects of drugs such as addiction, which has extremely important scientific significance and clinical value
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It is worth mentioning that this breakthrough is the culmination of the Zhu Shujia team’s dedicated and systematic study of the mechanism of action of NMDA receptors for many years

Duan Shumin,director of the Faculty of Medicine at Zhejiang University and academician of the Chinese Academy of Sciences, believes that in the research of the rapid antidepressant mechanism of ketamine, Chinese scientists have made continuous high-quality work output in recent years, showing that China's research in this field is at the forefront of the world

Related paper information: https://doi.