Abstract
Neuroinflammation is a common factor in neurodegenerative diseases, and it has been demonstrated that galectin-3 activates microglia and astrocytes, leading to inflammation. This means that inhibition of galectin-3 may become a new strategy for the treatment of neurodegenerative diseases. Based on this motivation, the objective of this study is to explore an integrated new approach for finding lead compounds that inhibit galectin-3, by combining universal artificial intelligence algorithms with traditional drug screening methods. Based on molecular docking method, potential compounds with high binding affinity were screened out from Chinese medicine database. Manifold artificial intelligence algorithms were performed to validate the docking results and further screen compounds. Among all involved predictive methods, the deep learning-based algorithm made 500 modeling attempts, and the square correlation coefficient of the best trained model on the test sets was 0.9. The XGBoost model reached a square correlation coefficient of 0.97 and a mean square error of only 0.01. We switched to the ZINC database and performed the same experiment, the results showed that the compounds in the former database showed stronger affinity. Finally, we further verified through molecular dynamics simulation that the complex composed of the candidate ligand and the target protein showed stable binding within 100 ns of simulation time. In summary, combined with the application based on artificial intelligence algorithms, we unearthed the active ingredients 1,2-Dimethylbenzene and Typhic acid contained in Crataegus pinnatifida and Typha angustata might be the effective inhibitors of neurodegenerative diseases. The high prediction accuracy of the models shows that it has practical application value on small sample data sets such as drug screening.
Highlights
Neurodegenerative diseases (ND) cause the progressive death of central neurons, leading to brain dysfunction and the development of diseases, such as Huntington’s disease (HD) (Macdonald et al, 1993), Alzheimer’s disease (AD) (McKhann et al, 1984) and Parkinson’s disease
The Rsquare of XGBoost model on the test sets was higher than other algorithms, and there was no overfitting on the training sets
The results showed that the molecules from the traditional Chinese medicine (TCM) database performed better than the ZINC database in terms of binding stability and pIC50 value predicted by artificial intelligence (AI) models
Summary
Neurodegenerative diseases (ND) cause the progressive death of central neurons, leading to brain dysfunction and the development of diseases, such as Huntington’s disease (HD) (Macdonald et al, 1993), Alzheimer’s disease (AD) (McKhann et al, 1984) and Parkinson’s disease. GRAPHICAL ABSTRACT | Graphical abstract of the role of Gal in HD pathogenesis. The level of Gal expressed by microglia is low under normal conditions. In HD patients, mutant Huntingtin (mHTT) continues to accumulate due to Huntingtin (HTT) mutations and NFκB is activated. NFκB triggers Gal aggregation, while Gal feedback promotes NFκB activation. MHTT causes lysosome damage, but Gal prevents the damaged lysosome from being cleared. NLRP3Inflammasome and proinflammatory factors (such as IL1β) increase in number, causing neuronal death and repair of damage
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