Large-Scale Off-Target Identification Using Fast And Accurate Dual Regularized One-Class Collaborative Filtering And Its Application To Drug Repurposing

Authors

Hansaim Lim, The Doctorate-Granting Institution of the City University of New YorkFollow
Aleksandar Poleksic, University of Northern IowaFollow
Yuan Yao, Nanjing University
Hanghang Tong, School of Computing, Informatics, and Decision Systems EngineeringFollow
Di He, The Doctorate-Granting Institution of the City University of New YorkFollow
Luke Zhuang, Academy for Information TechnologyFollow
Patrick Meng, High Technology High SchoolFollow
Lei Xie, The Doctorate-Granting Institution of the City University of New YorkFollow

Document Type

Article

Journal/Book/Conference Title

PLoS Computational Biology

Volume

12

Issue

10

Abstract

Target-based screening is one of the major approaches in drug discovery. Besides the intended target, unexpected drug off-target interactions often occur, and many of them have not been recognized and characterized. The off-target interactions can be responsible for either therapeutic or side effects. Thus, identifying the genome-wide off-targets of lead compounds or existing drugs will be critical for designing effective and safe drugs, and providing new opportunities for drug repurposing. Although many computational methods have been developed to predict drug-target interactions, they are either less accurate than the one that we are proposing here or computationally too intensive, thereby limiting their capability for large-scale off-target identification. In addition, the performances of most machine learning based algorithms have been mainly evaluated to predict off-target interactions in the same gene family for hundreds of chemicals. It is not clear how these algorithms perform in terms of detecting off-targets across gene families on a proteome scale. Here, we are presenting a fast and accurate off-target prediction method, REMAP, which is based on a dual regularized one-class collaborative filtering algorithm, to explore continuous chemical space, protein space, and their interactome on a large scale. When tested in a reliable, extensive, and cross-gene family benchmark, REMAP outperforms the state-of-the-art methods. Furthermore, REMAP is highly scalable. It can screen a dataset of 200 thousands chemicals against 20 thousands proteins within 2 hours. Using the reconstructed genome-wide target profile as the fingerprint of a chemical compound, we predicted that seven FDA-approved drugs can be repurposed as novel anti-cancer therapies. The anti-cancer activity of six of them is supported by experimental evidences. Thus, REMAP is a valuable addition to the existing in silico toolbox for drug target identification, drug repurposing, phenotypic screening, and side effect prediction. The software and benchmark are available at https://github.com/hansaimlim/REMAP.

Department

Department of Computer Science

Original Publication Date

10-1-2016

DOI of published version

10.1371/journal.pcbi.1005135

Repository

UNI ScholarWorks, Rod Library, University of Northern Iowa

Language

en

Recommended Citation

Lim, Hansaim; Poleksic, Aleksandar; Yao, Yuan; Tong, Hanghang; He, Di; Zhuang, Luke; Meng, Patrick; and Xie, Lei, "Large-Scale Off-Target Identification Using Fast And Accurate Dual Regularized One-Class Collaborative Filtering And Its Application To Drug Repurposing" (2016). Faculty Publications. 1017.
https://scholarworks.uni.edu/facpub/1017