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Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge

A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple rea...

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Autores principales: Xiong, Zhaoping, Jeon, Minji, Allaway, Robert J., Kang, Jaewoo, Park, Donghyeon, Lee, Jinhyuk, Jeon, Hwisang, Ko, Miyoung, Jiang, Hualiang, Zheng, Mingyue, Tan, Aik Choon, Guo, Xindi, Dang, Kristen K., Tropsha, Alex, Hecht, Chana, Das, Tirtha K., Carlson, Heather A., Abagyan, Ruben, Guinney, Justin, Schlessinger, Avner, Cagan, Ross
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483411/
https://www.ncbi.nlm.nih.gov/pubmed/34520464
http://dx.doi.org/10.1371/journal.pcbi.1009302
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author Xiong, Zhaoping
Jeon, Minji
Allaway, Robert J.
Kang, Jaewoo
Park, Donghyeon
Lee, Jinhyuk
Jeon, Hwisang
Ko, Miyoung
Jiang, Hualiang
Zheng, Mingyue
Tan, Aik Choon
Guo, Xindi
Dang, Kristen K.
Tropsha, Alex
Hecht, Chana
Das, Tirtha K.
Carlson, Heather A.
Abagyan, Ruben
Guinney, Justin
Schlessinger, Avner
Cagan, Ross
author_facet Xiong, Zhaoping
Jeon, Minji
Allaway, Robert J.
Kang, Jaewoo
Park, Donghyeon
Lee, Jinhyuk
Jeon, Hwisang
Ko, Miyoung
Jiang, Hualiang
Zheng, Mingyue
Tan, Aik Choon
Guo, Xindi
Dang, Kristen K.
Tropsha, Alex
Hecht, Chana
Das, Tirtha K.
Carlson, Heather A.
Abagyan, Ruben
Guinney, Justin
Schlessinger, Avner
Cagan, Ross
author_sort Xiong, Zhaoping
collection PubMed
description A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (‘polypharmacology’). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.
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spelling pubmed-84834112021-10-01 Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge Xiong, Zhaoping Jeon, Minji Allaway, Robert J. Kang, Jaewoo Park, Donghyeon Lee, Jinhyuk Jeon, Hwisang Ko, Miyoung Jiang, Hualiang Zheng, Mingyue Tan, Aik Choon Guo, Xindi Dang, Kristen K. Tropsha, Alex Hecht, Chana Das, Tirtha K. Carlson, Heather A. Abagyan, Ruben Guinney, Justin Schlessinger, Avner Cagan, Ross PLoS Comput Biol Research Article A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets (‘polypharmacology’). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology. Public Library of Science 2021-09-14 /pmc/articles/PMC8483411/ /pubmed/34520464 http://dx.doi.org/10.1371/journal.pcbi.1009302 Text en © 2021 Xiong et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Xiong, Zhaoping
Jeon, Minji
Allaway, Robert J.
Kang, Jaewoo
Park, Donghyeon
Lee, Jinhyuk
Jeon, Hwisang
Ko, Miyoung
Jiang, Hualiang
Zheng, Mingyue
Tan, Aik Choon
Guo, Xindi
Dang, Kristen K.
Tropsha, Alex
Hecht, Chana
Das, Tirtha K.
Carlson, Heather A.
Abagyan, Ruben
Guinney, Justin
Schlessinger, Avner
Cagan, Ross
Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title_full Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title_fullStr Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title_full_unstemmed Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title_short Crowdsourced identification of multi-target kinase inhibitors for RET- and TAU- based disease: The Multi-Targeting Drug DREAM Challenge
title_sort crowdsourced identification of multi-target kinase inhibitors for ret- and tau- based disease: the multi-targeting drug dream challenge
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483411/
https://www.ncbi.nlm.nih.gov/pubmed/34520464
http://dx.doi.org/10.1371/journal.pcbi.1009302
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