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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: Zhang, Haiping, Li, Junxin, Saravanan, Konda Mani, Wu, Hao, Wang, Zhichao, Wu, Du, Wei, Yanjie, Lu, Zhen, Chen, Youhai H., Wan, Xiaochun, Pan, Yi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650684/
https://www.ncbi.nlm.nih.gov/pubmed/34887765
http://dx.doi.org/10.3389/fphar.2021.772296
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author Zhang, Haiping
Li, Junxin
Saravanan, Konda Mani
Wu, Hao
Wang, Zhichao
Wu, Du
Wei, Yanjie
Lu, Zhen
Chen, Youhai H.
Wan, Xiaochun
Pan, Yi
author_facet Zhang, Haiping
Li, Junxin
Saravanan, Konda Mani
Wu, Hao
Wang, Zhichao
Wu, Du
Wei, Yanjie
Lu, Zhen
Chen, Youhai H.
Wan, Xiaochun
Pan, Yi
author_sort Zhang, Haiping
collection PubMed
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.
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spelling pubmed-86506842021-12-08 An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2 Zhang, Haiping Li, Junxin Saravanan, Konda Mani Wu, Hao Wang, Zhichao Wu, Du Wei, Yanjie Lu, Zhen Chen, Youhai H. Wan, Xiaochun Pan, Yi Front Pharmacol Pharmacology 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. Frontiers Media S.A. 2021-11-23 /pmc/articles/PMC8650684/ /pubmed/34887765 http://dx.doi.org/10.3389/fphar.2021.772296 Text en Copyright © 2021 Zhang, Li, Saravanan, Wu, Wang, Wu, Wei, Lu, Chen, Wan and Pan. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Zhang, Haiping
Li, Junxin
Saravanan, Konda Mani
Wu, Hao
Wang, Zhichao
Wu, Du
Wei, Yanjie
Lu, Zhen
Chen, Youhai H.
Wan, Xiaochun
Pan, Yi
An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
title 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_short 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
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650684/
https://www.ncbi.nlm.nih.gov/pubmed/34887765
http://dx.doi.org/10.3389/fphar.2021.772296
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