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

doi:10.3389/fphar.2021.772296

	An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2
	Zhang, Haiping 1; Li, Junxin 2; Saravanan, Konda Mani 1; Wu, Hao 1; Wang, Zhichao 1; Wu, Du 1; Wei, Yanjie 1; Lu, Zhen 3; Chen, Youhai H.3; Wan, Xiaochun 2; Pan, Yi 1
	2021-11-23
发表期刊	FRONTIERS IN PHARMACOLOGY
卷号	12 页码:13
摘要	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 mu M 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.
关键词	TIPE2 UM-164 virtual screening deep learning molecular dynamics simulation
DOI	10.3389/fphar.2021.772296
收录类别	SCI
语种	英语
资助项目	Shenzhen KQTD Project[KQTD20200820113106007] ; National Key R&D Program of China[2019YFA0906100] ; Key-Area Research and Development Program of Guangdong Province[2019B020201014] ; Guangdong Basic and Applied Basic Research Foundation[2020A1515110840] ; Shenzhen Basic Research Fund[KQTD20200820113106007] ; Shenzhen Basic Research Fund[JCYJ20190807170801656] ; Shenzhen Basic Research Fund[RCYX2020071411473419] ; National Key Research and Development Program of China[2018YFB0204403] ; Research Funding of Shenzhen[JCYJ201803053000708] ; Strategic Priority CAS[XDB38000000] ; National Science Foundation of China[U1813203] ; CAS Key Lab[2011DP173015]
WOS研究方向	Pharmacology & Pharmacy
WOS类目	Pharmacology & Pharmacy
WOS记录号	WOS:000727671000001
出版者	FRONTIERS MEDIA SA
引用统计	被引频次：17[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.204/handle/2XEOYT63/18023
专题	中国科学院计算技术研究所期刊论文_英文
通讯作者	Chen, Youhai H.; Wan, Xiaochun; Pan, Yi
作者单位	1.Chinese Acad Sci, Shenzhen Inst Adv Technol, Joint Engn Res Ctr Hlth Big Data Intelligent Anal, Ctr High Performance Comp, Shenzhen, Peoples R China 2.Chinese Acad Sci, Univ City Shenzhen, Shenzhen Inst Adv Technol, Inst Biomed & Biotechnol,Shenzhen Lab Human Antib, Shenzhen, Peoples R China 3.Chinese Acad Sci, Univ City Shenzhen, Shenzhen Inst Adv Technol, Ctr Canc Immunol, Shenzhen, Peoples R China
推荐引用方式 GB/T 7714	Zhang, Haiping,Li, Junxin,Saravanan, Konda Mani,et al. An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2[J]. FRONTIERS IN PHARMACOLOGY,2021,12:13.
APA	Zhang, Haiping.,Li, Junxin.,Saravanan, Konda Mani.,Wu, Hao.,Wang, Zhichao.,...&Pan, Yi.(2021).An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2.FRONTIERS IN PHARMACOLOGY,12,13.
MLA	Zhang, Haiping,et al."An Integrated Deep Learning and Molecular Dynamics Simulation-Based Screening Pipeline Identifies Inhibitors of a New Cancer Drug Target TIPE2".FRONTIERS IN PHARMACOLOGY 12(2021):13.