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Editor-in-Chief | About 50 million people worldwide have dementia, and this number is expected to increase to 152 million by 2050
.
Despite the rising incidence, AD drug development has been in trouble for a long time
.
From 2000 to 2017, 33 top pharmaceutical companies have invested more than $600 billion in research and development in the AD field
.
Because the specific pathogenesis of AD remains unclear, drug development in this field has repeatedly failed
.
In the process of nerve cell aging, mitochondria, the "power plant" in the cell, will continue to accumulate damage and aggravate nerve cell death
.
To keep mitochondria in good condition, cells maintain neuronal health by selectively removing aging-damaged mitochondria through an ingenious quality control system called mitophagy
.
Fang Fei's team previously found that the impaired mitophagy mechanism plays a key role in the pathogenesis of Alzheimer's disease [1]
.
Therefore, enhancing mitophagy may be an effective therapeutic strategy for AD
.
However, due to the lack of clear drug targets, how to quickly and efficiently discover small-molecule mitophagy agonists with AD therapeutic potential is a major challenge
.
In order to solve this challenge, on January 6, 2022, the team of associate professor Fang Fei of the University of Oslo in Norway and the team of Lu Jiahong, associate professor of the Chinese Medical Research Institute of the University of Macau published online in the journal Nature Biomedical Engineering entitled Amelioration of Alzheimer's disease pathology by mitophagy inducers identified Long research paper on via machine learning and a cross-species workflow
.
This study established a virtual screening algorithm based on artificial intelligence (AI) fusion of multi-dimensional molecular information, combined with cell, nematode, mouse multi-species Alzheimer's disease (AD) model validation, successfully screened and obtained AD therapeutic potential.
Small molecule compounds of traditional Chinese medicine
.
This study proposes an efficient and feasible AI-based drug discovery solution for AD treatment, which provides a new strategy for the rapid development of anti-AD drugs
.
Small molecules of traditional Chinese medicine are rich in structural diversity and relatively low in toxic and side effects, making them a good source for drug discovery
.
Jiahong Lu's team from the University of Macau has long focused on the discovery and pharmacological activity of natural small molecule autophagy regulators, and has established a compound library of natural small molecules including alkaloids, flavonoids, terpenoids and other types of compounds
.
For the first time, the team established a new AI technology for drug screening: machine learning of one-dimensional, two-dimensional and three-dimensional information of drug molecules
.
The pre-trained data comes from a total of 19 million small molecule data from ChEMBL and ZINC
.
The pre-trained representation model comprehensively considers the information of various dimensions of molecules, including one-dimensional sequence information (SMILES), two-dimensional molecular topological similarity, and three-dimensional spatial information
.
The development and verification of the AI algorithm model is in charge of the Hangzhou Derui Medicine team
.
Through AI virtual screening, the team successfully screened 18 natural small molecule compounds from a total of 3724 natural small molecule compounds in the Chinese Medicine Small Molecule Compound Library of the University of Macau, and finally found two compounds, kaempferol and danyemodin through experiments.
It can improve memory and cognitive impairment in nematode and mouse AD models within a safe dose range, and alleviate AD pathological phenotypes
.
Drug research and development is costly, has a long cycle, and has a high failure rate
.
Virtual screening of drugs through AI can not only speed up intermediate steps, but also greatly reduce R&D costs while improving the accuracy of drug screening
.
In the early stage of this study, AI was used for efficient and low-cost screening, and later, traditional wet laboratory verification (cells, nematodes and mice) was carried out to improve the accuracy of screening drugs.
The combination of the two parts can greatly accelerate the speed of drug development and increase the success rate of research and development
.
This design idea can be applied not only in the drug discovery of Alzheimer's disease, but also in the drug discovery of other diseases
.
The study received positive reviews from international peers
.
Li-Huei Tsai (MIT, MIT), an international authority on Alzheimer's disease research and a professor in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology, pointed out: "This study used cutting-edge machine learning algorithms to successfully discover new neurons that induce mitochondrial autophagy.
The drug candidates were screened by computer, and then validated in multiple systems using cells, Caenorhabditis elegans, and mouse models expressing human P301L Tau protein, and finally two small-molecule compounds, kaempferol and emodin, were found
.
Interestingly, these mitophagy inducers can effectively improve neuronal function, reduce AD-related pathological changes, and enhance learning and memory ability in animal models
.
Therefore, this study was screened by computer and validated by multiple systems, thereby A potent inducer of mitophagy was identified
.
Furthermore, their study illustrates the therapeutic value of mitophagy in neuronal protection and improved memory function
.
The first authors of the paper are Xie Chenglong, Deputy Chief Physician of the First Affiliated Hospital of Wenzhou Medical University, Zhuang Xuxu, a doctoral student at the University of Macau, Niu Zhangming, the founder of Derui Medicine Technology Co.
, Ltd.
, and Ai Ruixue, a doctoral student at the University of Oslo
.
The corresponding authors are Dr.
Fang Fei and Dr.
Jiahong Lu
.
Among them, the development and verification of the AI algorithm model is the responsibility of the Derui Medicine team
.
Link to the original text: https:// Reference 1.
Fang, EF, Hou, Y.
, Palikaras, K.
, Adriaanse, BA, Kerr, JS, Yang, B.
, Lautrup, S.
, Hasan-Olive, MM, Caponio, D.
, Dan, X.
, Rocktäschel, P.
, Croteau, DL, Akbari, M.
, Greig, NH, Fladby, T.
, Nilsen, H .
, Cader, MZ, Mattson, MP, Tavernarakis, N.
, & Bohr, VA (2019).
Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
Nature neuroscience, 22(3), 401 –412.
https://doi.
org/10.
1038/s41593-018-0332-9 Instructions for reprinting [Non-original article] The copyright of this article belongs to the author of the article.
Individuals are welcome to forward and share it.
Reprinting is prohibited without permission.
The author has all legal rights , violators will be prosecuted
.
.
Despite the rising incidence, AD drug development has been in trouble for a long time
.
From 2000 to 2017, 33 top pharmaceutical companies have invested more than $600 billion in research and development in the AD field
.
Because the specific pathogenesis of AD remains unclear, drug development in this field has repeatedly failed
.
In the process of nerve cell aging, mitochondria, the "power plant" in the cell, will continue to accumulate damage and aggravate nerve cell death
.
To keep mitochondria in good condition, cells maintain neuronal health by selectively removing aging-damaged mitochondria through an ingenious quality control system called mitophagy
.
Fang Fei's team previously found that the impaired mitophagy mechanism plays a key role in the pathogenesis of Alzheimer's disease [1]
.
Therefore, enhancing mitophagy may be an effective therapeutic strategy for AD
.
However, due to the lack of clear drug targets, how to quickly and efficiently discover small-molecule mitophagy agonists with AD therapeutic potential is a major challenge
.
In order to solve this challenge, on January 6, 2022, the team of associate professor Fang Fei of the University of Oslo in Norway and the team of Lu Jiahong, associate professor of the Chinese Medical Research Institute of the University of Macau published online in the journal Nature Biomedical Engineering entitled Amelioration of Alzheimer's disease pathology by mitophagy inducers identified Long research paper on via machine learning and a cross-species workflow
.
This study established a virtual screening algorithm based on artificial intelligence (AI) fusion of multi-dimensional molecular information, combined with cell, nematode, mouse multi-species Alzheimer's disease (AD) model validation, successfully screened and obtained AD therapeutic potential.
Small molecule compounds of traditional Chinese medicine
.
This study proposes an efficient and feasible AI-based drug discovery solution for AD treatment, which provides a new strategy for the rapid development of anti-AD drugs
.
Small molecules of traditional Chinese medicine are rich in structural diversity and relatively low in toxic and side effects, making them a good source for drug discovery
.
Jiahong Lu's team from the University of Macau has long focused on the discovery and pharmacological activity of natural small molecule autophagy regulators, and has established a compound library of natural small molecules including alkaloids, flavonoids, terpenoids and other types of compounds
.
For the first time, the team established a new AI technology for drug screening: machine learning of one-dimensional, two-dimensional and three-dimensional information of drug molecules
.
The pre-trained data comes from a total of 19 million small molecule data from ChEMBL and ZINC
.
The pre-trained representation model comprehensively considers the information of various dimensions of molecules, including one-dimensional sequence information (SMILES), two-dimensional molecular topological similarity, and three-dimensional spatial information
.
The development and verification of the AI algorithm model is in charge of the Hangzhou Derui Medicine team
.
Through AI virtual screening, the team successfully screened 18 natural small molecule compounds from a total of 3724 natural small molecule compounds in the Chinese Medicine Small Molecule Compound Library of the University of Macau, and finally found two compounds, kaempferol and danyemodin through experiments.
It can improve memory and cognitive impairment in nematode and mouse AD models within a safe dose range, and alleviate AD pathological phenotypes
.
Drug research and development is costly, has a long cycle, and has a high failure rate
.
Virtual screening of drugs through AI can not only speed up intermediate steps, but also greatly reduce R&D costs while improving the accuracy of drug screening
.
In the early stage of this study, AI was used for efficient and low-cost screening, and later, traditional wet laboratory verification (cells, nematodes and mice) was carried out to improve the accuracy of screening drugs.
The combination of the two parts can greatly accelerate the speed of drug development and increase the success rate of research and development
.
This design idea can be applied not only in the drug discovery of Alzheimer's disease, but also in the drug discovery of other diseases
.
The study received positive reviews from international peers
.
Li-Huei Tsai (MIT, MIT), an international authority on Alzheimer's disease research and a professor in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology, pointed out: "This study used cutting-edge machine learning algorithms to successfully discover new neurons that induce mitochondrial autophagy.
The drug candidates were screened by computer, and then validated in multiple systems using cells, Caenorhabditis elegans, and mouse models expressing human P301L Tau protein, and finally two small-molecule compounds, kaempferol and emodin, were found
.
Interestingly, these mitophagy inducers can effectively improve neuronal function, reduce AD-related pathological changes, and enhance learning and memory ability in animal models
.
Therefore, this study was screened by computer and validated by multiple systems, thereby A potent inducer of mitophagy was identified
.
Furthermore, their study illustrates the therapeutic value of mitophagy in neuronal protection and improved memory function
.
The first authors of the paper are Xie Chenglong, Deputy Chief Physician of the First Affiliated Hospital of Wenzhou Medical University, Zhuang Xuxu, a doctoral student at the University of Macau, Niu Zhangming, the founder of Derui Medicine Technology Co.
, Ltd.
, and Ai Ruixue, a doctoral student at the University of Oslo
.
The corresponding authors are Dr.
Fang Fei and Dr.
Jiahong Lu
.
Among them, the development and verification of the AI algorithm model is the responsibility of the Derui Medicine team
.
Link to the original text: https:// Reference 1.
Fang, EF, Hou, Y.
, Palikaras, K.
, Adriaanse, BA, Kerr, JS, Yang, B.
, Lautrup, S.
, Hasan-Olive, MM, Caponio, D.
, Dan, X.
, Rocktäschel, P.
, Croteau, DL, Akbari, M.
, Greig, NH, Fladby, T.
, Nilsen, H .
, Cader, MZ, Mattson, MP, Tavernarakis, N.
, & Bohr, VA (2019).
Mitophagy inhibits amyloid-β and tau pathology and reverses cognitive deficits in models of Alzheimer's disease.
Nature neuroscience, 22(3), 401 –412.
https://doi.
org/10.
1038/s41593-018-0332-9 Instructions for reprinting [Non-original article] The copyright of this article belongs to the author of the article.
Individuals are welcome to forward and share it.
Reprinting is prohibited without permission.
The author has all legal rights , violators will be prosecuted
.
