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Target Identification Among Known Drugs by Deep Learning from Heterogeneous Networks

100 Pages Posted: 13 May 2019 Sneak Peek Status: Review Complete

See all articles by Xiangxiang Zeng

Xiangxiang Zeng

Xiamen University - Department of Computer Science

Siyi Zhu

Xiamen University - Department of Computer Science

Weiqiang Lu

East China Normal University (ECNU) - Shanghai Key Laboratory of Regulatory Biology

Jin Huang

East China University of Science and Technology (ECUST), School of Pharmacy, Shanghai Key Laboratory of New Drug Design

Zehui Liu

East China University of Science and Technology (ECUST), School of Pharmacy, Shanghai Key Laboratory of New Drug Design

Yadi Zhou

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Yuan Hou

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Yin Huang

China Pharmaceutical University - Key Laboratory of Drug Quality Control and Pharmacovigilance

Huimin Guo

China Pharmaceutical University - Key Laboratory of Drug Quality Control and Pharmacovigilance

Jiansong Fang

Guangzhou University of Chinese Medicine - Institute of Clinical Pharmacology; Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Mingyao Liu

East China Normal University (ECNU) - Shanghai Key Laboratory of Regulatory Biology; Texas A&M University (TAMU), Health Sciences Center, College of Medicine, Department of Cellular and Molecular Medicine

Bruce Trapp

Cleveland Clinic - Department of Neurosciences

Lang Li

Ohio State University (OSU) - Department of Biomedical Informatics

Ruth Nussinov

National Institutes of Health (NIH) - National Cancer Institute at Frederick ; Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Charis Eng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute; Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center; Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences; Cleveland Clinic - Taussig Cancer Institute

Joseph Loscalzo

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine

Feixiong Cheng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute; Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine; Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

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Abstract

Without foreknowledge of the complete drug-target network, development of promising and affordable approaches for effective treatment of human diseases is challenging. Here, we develop deepDTnet, a deep learning methodology for new target identification and drug repurposing in a heterogeneous drug-gene-disease network embedding 15 types of chemical, genomic, phenotypic, and cellular network profiles. Trained on 732 U.S. Food and Drug Administration-approved small molecule drugs, deepDTnet shows high accuracy (AUC = 0.963) in identifying novel molecular targets for known drugs, outperforming previously published methodologies. We then experimentally validate that deepDTnet-predicted topotecan (an approved topoisomerase inhibitor) is a new, direct inhibitor (IC50=0.43 µM) of human RAR-related orphan receptor-gamma t (ROR-γt). Furthermore, by specifically targeting ROR-γt, topotecan reveals a potential therapeutic effect in a mouse model of multiple sclerosis. In summary, deepDTnet offers a powerful deep learning methodology for network-based target identification to accelerate drug repurposing and minimize the translational gap in drug development.

Keywords: drug-target network, deep learning, heterogeneous networks, topotecan, ROR-γt, multiple sclerosis

Suggested Citation

Zeng, Xiangxiang and Zhu, Siyi and Lu, Weiqiang and Huang, Jin and Liu, Zehui and Zhou, Yadi and Hou, Yuan and Huang, Yin and Guo, Huimin and Fang, Jiansong and Liu, Mingyao and Trapp, Bruce and Li, Lang and Nussinov, Ruth and Eng, Charis and Loscalzo, Joseph and Cheng, Feixiong, Target Identification Among Known Drugs by Deep Learning from Heterogeneous Networks (May 9, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00154. Available at SSRN: https://ssrn.com/abstract=3385690 or http://dx.doi.org/10.2139/ssrn.3385690
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Xiangxiang Zeng

Xiamen University - Department of Computer Science ( email )

Fujian
China

Siyi Zhu

Xiamen University - Department of Computer Science ( email )

Fujian
China

Weiqiang Lu

East China Normal University (ECNU) - Shanghai Key Laboratory of Regulatory Biology ( email )

Shanghai
China

Jin Huang

East China University of Science and Technology (ECUST), School of Pharmacy, Shanghai Key Laboratory of New Drug Design

Shanghai
China

Zehui Liu

East China University of Science and Technology (ECUST), School of Pharmacy, Shanghai Key Laboratory of New Drug Design ( email )

Shanghai
China

Yadi Zhou

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute ( email )

Cleveland, OH 44106
United States

Yuan Hou

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Cleveland, OH 44106
United States

Yin Huang

China Pharmaceutical University - Key Laboratory of Drug Quality Control and Pharmacovigilance

Nanjing
China

Huimin Guo

China Pharmaceutical University - Key Laboratory of Drug Quality Control and Pharmacovigilance ( email )

Nanjing
China

Jiansong Fang

Guangzhou University of Chinese Medicine - Institute of Clinical Pharmacology ( email )

Guangzhou
China

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute ( email )

Cleveland, OH 44106
United States

Mingyao Liu

East China Normal University (ECNU) - Shanghai Key Laboratory of Regulatory Biology ( email )

Shanghai
China

Texas A&M University (TAMU), Health Sciences Center, College of Medicine, Department of Cellular and Molecular Medicine ( email )

Langford Building A
798 Ross St.
College Station, TX 77843-3137
United States

Bruce Trapp

Cleveland Clinic - Department of Neurosciences ( email )

Cleveland, OH
United States

Lang Li

Ohio State University (OSU) - Department of Biomedical Informatics

Columbus, OH
United States

Ruth Nussinov

National Institutes of Health (NIH) - National Cancer Institute at Frederick

Frederick, MD 21702-1201
United States

Tel Aviv University - Department of Human Molecular Genetics and Biochemistry

Tel Aviv, 69978
Israel

Charis Eng

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute

Cleveland, OH 44106
United States

Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center

Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Department of Genetics and Genome Sciences

2511 Overlook Road
Cleveland Heights, OH
United States

Cleveland Clinic - Taussig Cancer Institute

9500 Euclid Avenue
Cleveland, OH 44195
United States

Joseph Loscalzo

Harvard University, Harvard Medical School, Brigham and Women's Hospital, Department of Medicine ( email )

Boston, MA 02115
United States

Feixiong Cheng (Contact Author)

Cleveland Clinic, Lerner Research Institute, Genomic Medicine Institute ( email )

Cleveland, OH 44106
United States

Cleveland Clinic, Lerner College of Medicine, Department of Molecular Medicine ( email )

9500 Euclid Avenue
Cleveland, OH 44195
United States

Case Western Reserve University, School of Medicine, Case Comprehensive Cancer Center ( email )

2511 Overlook Road
Cleveland Heights, OH 44195
United States

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