ArticleJournal of chemical information and modeling2015
Relating Essential Proteins to Drug Side-Effects Using Canonical Component Analysis: A Structure-Based Approach.
Article in Journal of chemical information and modeling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 40 citations in OpenAlex.
- Multiscale analysis and optimal glioma therapeutic candidate discovery using the CANDO platform.Journal of cheminformatics · 2026Article
- Machine Learning Prediction of On/Off Target-driven Clinical Adverse Events.Pharmaceutical research · 2024Article
- Prediction of drug side effects with transductive matrix co-completion.Bioinformatics (Oxford, England) · 2023Article
- A Deep-Learning Proteomic-Scale Approach for Drug Design.Pharmaceuticals (Basel, Switzerland) · 2021Article
- cando.py: Open Source Software for Predictive Bioanalytics of Large Scale Drug-Protein-Disease Data.Journal of chemical information and modeling · 2020Article
- Identifying Protein Features Responsible for Improved Drug Repurposing Accuracies Using the CANDO Platform: Implications for Drug Design.Molecules (Basel, Switzerland) · 2019Article
- PathFX provides mechanistic insights into drug efficacy and safety for regulatory review and therapeutic development.PLoS computational biology · 2018Article
- Association Between Serotonin Syndrome and Second-Generation Antipsychotics via Pharmacological Target-Adverse Event Analysis.Clinical and translational science · 2018Article
- Biological and functional relevance of CASP predictions.Proteins · 2018Article
- Exploring Landscape of Drug-Target-Pathway-Side Effect Associations.AMIA Joint Summits on Translational Science proceedings. AMIA Joint Summits on Translational Science · 2018Article
- Evolutionarily Conserved Roles for Blood-Brain Barrier Xenobiotic Transporters in Endogenous Steroid Partitioning and Behavior.Cell reports · 2017Article
- Systematic Analyses and Prediction of Human Drug Side Effect Associated Proteins from the Perspective of Protein Evolution.Genome biology and evolution · 2017Article
- Estimation of Maximum Recommended Therapeutic Dose Using Predicted Promiscuity and Potency.Clinical and translational science · 2016Article
- Drug-induced adverse events prediction with the LINCS L1000 data.Bioinformatics (Oxford, England) · 2016Article
- The SIDER database of drugs and side effects.Nucleic acids research · 2016Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The molecular mechanism of many drug side-effects is unknown and difficult to predict. Previous methods for explaining side-effects have focused on known drug targets and their pathways. However, low affinity binding to proteins that are not usually considered drug targets may also drive side-effects. In order to assess these alternative targets, we used the 3D structures of 563 essential human proteins systematically to predict binding to 216 drugs. We first benchmarked our affinity predictions with available experimental data. We then combined singular value decomposition and canonical component analysis (SVD-CCA) to predict side-effects based on these novel target profiles. Our method predicts side-effects with good accuracy (average AUC: 0.82 for side effects present in <50% of drug labels). We also noted that side-effect frequency is the most important feature for prediction and can confound efforts at elucidating mechanism; our method allows us to remove the contribution of frequency and isolate novel biological signals. In particular, our analysis produces 2768 triplet associations between 50 essential proteins, 99 drugs, and 77 side-effects. Although experimental validation is difficult because many of our essential proteins do not have validated assays, we nevertheless attempted to validate a subset of these associations using experimental assay data. Our focus on essential proteins allows us to find potential associations that would likely be missed if we used recognized drug targets. Our associations provide novel insights about the molecular mechanisms of drug side-effects and highlight the need for expanded experimental efforts to investigate drug binding to proteins more broadly.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.