An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2

The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly...

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Autores principales: Haiping Zhang, Junxin Li, Konda Mani Saravanan, Hao Wu, Zhichao Wang, Du Wu, Yanjie Wei, Zhen Lu, Youhai H. Chen, Xiaochun Wan, Yi Pan
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Publicado: Frontiers Media S.A. 2021
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spelling oai:doaj.org-article:1139ef86755d49f2b3368ed770d9f5be2021-11-30T14:09:35ZAn Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE21663-981210.3389/fphar.2021.772296https://doaj.org/article/1139ef86755d49f2b3368ed770d9f5be2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.772296/fullhttps://doaj.org/toc/1663-9812The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly identify novel drug candidates against TIPE2 protein. With the current advances in deep learning and molecular dynamics simulation-based drug screening, large-scale exploration of inhibitory candidates for TIPE2 becomes possible. In this work, we apply deep learning-based methods to perform a preliminary screening against TIPE2 over several commercially available compound datasets. Then, we carried a fine screening by molecular dynamics simulations, followed by metadynamics simulations. Finally, four compounds were selected for experimental validation from 64 candidates obtained from the screening. With surprising accuracy, three compounds out of four can bind to TIPE2. Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development.Haiping ZhangJunxin LiKonda Mani SaravananHao WuZhichao WangDu WuYanjie WeiZhen LuYouhai H. ChenXiaochun WanYi PanFrontiers Media S.A.articleTIPE2UM-164virtual screeningdeep learningmolecular dynamics simulationTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution DOAJ
collection DOAJ
language EN
topic TIPE2
UM-164
virtual screening
deep learning
molecular dynamics simulation
Therapeutics. Pharmacology
RM1-950
spellingShingle TIPE2
UM-164
virtual screening
deep learning
molecular dynamics simulation
Therapeutics. Pharmacology
RM1-950
Haiping Zhang
Junxin Li
Konda Mani Saravanan
Hao Wu
Zhichao Wang
Du Wu
Yanjie Wei
Zhen Lu
Youhai H. Chen
Xiaochun Wan
Yi Pan
An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
description The TIPE2 (tumor necrosis factor-alpha-induced protein 8-like 2) protein is a major regulator of cancer and inflammatory diseases. The availability of its sequence and structure, as well as the critical amino acids involved in its ligand binding, provides insights into its function and helps greatly identify novel drug candidates against TIPE2 protein. With the current advances in deep learning and molecular dynamics simulation-based drug screening, large-scale exploration of inhibitory candidates for TIPE2 becomes possible. In this work, we apply deep learning-based methods to perform a preliminary screening against TIPE2 over several commercially available compound datasets. Then, we carried a fine screening by molecular dynamics simulations, followed by metadynamics simulations. Finally, four compounds were selected for experimental validation from 64 candidates obtained from the screening. With surprising accuracy, three compounds out of four can bind to TIPE2. Among them, UM-164 exhibited the strongest binding affinity of 4.97 µM and was able to interfere with the binding of TIPE2 and PIP2 according to competitive bio-layer interferometry (BLI), which indicates that UM-164 is a potential inhibitor against TIPE2 function. The work demonstrates the feasibility of incorporating deep learning and MD simulation in virtual drug screening and provides high potential inhibitors against TIPE2 for drug development.
format article
author Haiping Zhang
Junxin Li
Konda Mani Saravanan
Hao Wu
Zhichao Wang
Du Wu
Yanjie Wei
Zhen Lu
Youhai H. Chen
Xiaochun Wan
Yi Pan
author_facet Haiping Zhang
Junxin Li
Konda Mani Saravanan
Hao Wu
Zhichao Wang
Du Wu
Yanjie Wei
Zhen Lu
Youhai H. Chen
Xiaochun Wan
Yi Pan
author_sort Haiping Zhang
title An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title_short An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title_full An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title_fullStr An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title_full_unstemmed An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title_sort integrated deep learning and molecular dynamics simulation-based screening pipeline identifies inhibitors of a new cancer drug target tipe2
publisher Frontiers Media S.A.
publishDate 2021
url https://doaj.org/article/1139ef86755d49f2b3368ed770d9f5be
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