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GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery

BACKGROUND: Accurately predicting drug-target binding affinity (DTA) in silico plays an important role in drug discovery. Most of the computational methods developed for predicting DTA use machine learning models, especially deep neural networks, and depend on large-scale labelled data. However, it...

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Autores principales: Lin, Shaofu, Shi, Chengyu, Chen, Jianhui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449940/
https://www.ncbi.nlm.nih.gov/pubmed/36071406
http://dx.doi.org/10.1186/s12859-022-04905-6
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author Lin, Shaofu
Shi, Chengyu
Chen, Jianhui
author_facet Lin, Shaofu
Shi, Chengyu
Chen, Jianhui
author_sort Lin, Shaofu
collection PubMed
description BACKGROUND: Accurately predicting drug-target binding affinity (DTA) in silico plays an important role in drug discovery. Most of the computational methods developed for predicting DTA use machine learning models, especially deep neural networks, and depend on large-scale labelled data. However, it is difficult to learn enough feature representation from tens of millions of compounds and hundreds of thousands of proteins only based on relatively limited labelled drug-target data. There are a large number of unknown drugs, which never appear in the labelled drug-target data. This is a kind of out-of-distribution problems in bio-medicine. Some recent studies adopted self-supervised pre-training tasks to learn structural information of amino acid sequences for enhancing the feature representation of proteins. However, the task gap between pre-training and DTA prediction brings the catastrophic forgetting problem, which hinders the full application of feature representation in DTA prediction and seriously affects the generalization capability of models for unknown drug discovery. RESULTS: To address these problems, we propose the GeneralizedDTA, which is a new DTA prediction model oriented to unknown drug discovery, by combining pre-training and multi-task learning. We introduce self-supervised protein and drug pre-training tasks to learn richer structural information from amino acid sequences of proteins and molecular graphs of drug compounds, in order to alleviate the problem of high variance caused by encoding based on deep neural networks and accelerate the convergence of prediction model on small-scale labelled data. We also develop a multi-task learning framework with a dual adaptation mechanism to narrow the task gap between pre-training and prediction for preventing overfitting and improving the generalization capability of DTA prediction model on unknown drug discovery. To validate the effectiveness of our model, we construct an unknown drug data set to simulate the scenario of unknown drug discovery. Compared with existing DTA prediction models, the experimental results show that our model has the higher generalization capability in the DTA prediction of unknown drugs. CONCLUSIONS: The advantages of our model are mainly attributed to two kinds of pre-training tasks and the multi-task learning framework, which can learn richer structural information of proteins and drugs from large-scale unlabeled data, and then effectively integrate it into the downstream prediction task for obtaining a high-quality DTA prediction in unknown drug discovery.
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spelling pubmed-94499402022-09-07 GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery Lin, Shaofu Shi, Chengyu Chen, Jianhui BMC Bioinformatics Research BACKGROUND: Accurately predicting drug-target binding affinity (DTA) in silico plays an important role in drug discovery. Most of the computational methods developed for predicting DTA use machine learning models, especially deep neural networks, and depend on large-scale labelled data. However, it is difficult to learn enough feature representation from tens of millions of compounds and hundreds of thousands of proteins only based on relatively limited labelled drug-target data. There are a large number of unknown drugs, which never appear in the labelled drug-target data. This is a kind of out-of-distribution problems in bio-medicine. Some recent studies adopted self-supervised pre-training tasks to learn structural information of amino acid sequences for enhancing the feature representation of proteins. However, the task gap between pre-training and DTA prediction brings the catastrophic forgetting problem, which hinders the full application of feature representation in DTA prediction and seriously affects the generalization capability of models for unknown drug discovery. RESULTS: To address these problems, we propose the GeneralizedDTA, which is a new DTA prediction model oriented to unknown drug discovery, by combining pre-training and multi-task learning. We introduce self-supervised protein and drug pre-training tasks to learn richer structural information from amino acid sequences of proteins and molecular graphs of drug compounds, in order to alleviate the problem of high variance caused by encoding based on deep neural networks and accelerate the convergence of prediction model on small-scale labelled data. We also develop a multi-task learning framework with a dual adaptation mechanism to narrow the task gap between pre-training and prediction for preventing overfitting and improving the generalization capability of DTA prediction model on unknown drug discovery. To validate the effectiveness of our model, we construct an unknown drug data set to simulate the scenario of unknown drug discovery. Compared with existing DTA prediction models, the experimental results show that our model has the higher generalization capability in the DTA prediction of unknown drugs. CONCLUSIONS: The advantages of our model are mainly attributed to two kinds of pre-training tasks and the multi-task learning framework, which can learn richer structural information of proteins and drugs from large-scale unlabeled data, and then effectively integrate it into the downstream prediction task for obtaining a high-quality DTA prediction in unknown drug discovery. BioMed Central 2022-09-07 /pmc/articles/PMC9449940/ /pubmed/36071406 http://dx.doi.org/10.1186/s12859-022-04905-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Lin, Shaofu
Shi, Chengyu
Chen, Jianhui
GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title_full GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title_fullStr GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title_full_unstemmed GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title_short GeneralizedDTA: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
title_sort generalizeddta: combining pre-training and multi-task learning to predict drug-target binding affinity for unknown drug discovery
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9449940/
https://www.ncbi.nlm.nih.gov/pubmed/36071406
http://dx.doi.org/10.1186/s12859-022-04905-6
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