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

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.Author Summary: High-throughput techniques have generated vast amounts of diverse omics and phenotypic data. However, these sets of data have not yet been fully explored to improve the effectiveness and efficiency of drug discovery, a process which has traditionally adopted a one-drug-one-gene paradigm. Consequently, the cost of bringing a drug to market is astounding and the failure rate is daunting. The failure of the target-based drug discovery is in large part due to the fact that a drug rarely interacts only with its intended receptor, but also generally binds to other receptors. To rationally design potent and safe therapeutics, we need to identify all the possible cellular proteins interacting with a drug in an organism. Existing experimental techniques are not sufficient to address this problem, and will benefit from computational modeling. However, it is a daunting task to reliably screen millions of chemicals against hundreds of thousands of proteins. Here, we introduce a fast and accurate method REMAP for large-scale predictions of drug-target interactions. REMAP outperforms state-of-the-art algorithms in terms of both speed and accuracy, and has been successfully applied to drug repurposing. Thus, REMAP may have broad applications in drug discovery.