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Large-scale prediction and testing of drug activity on side-effect targets.

ABSTRACT: Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 ?M. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.

SUBMITTER: Lounkine E

PROVIDER: S-EPMC3383642 | biostudies-other | 2012 Jun

REPOSITORIES: biostudies-other

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Large-scale prediction and testing of drug activity on side-effect targets.

Lounkine Eugen E Keiser Michael J MJ Whitebread Steven S Mikhailov Dmitri D Hamon Jacques J Jenkins Jeremy L JL Lavan Paul P Weber Eckhard E Doak Allison K AK Côté Serge S Shoichet Brian K BK Urban Laszlo L

Nature 20120610 7403

Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases u ...[more]

PMID: 22722194

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Project description:BACKGROUND:Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects. METHODS:We perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects. RESULTS:We observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score???3.0) and corroborating docking results (RMSD?<?2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases. CONCLUSIONS:The detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.

Project description:BACKGROUND:In silico prediction of potential drug side-effects is of crucial importance for drug development, since wet experimental identification of drug side-effects is expensive and time-consuming. Existing computational methods mainly focus on leveraging validated drug side-effect relations for the prediction. The performance is severely impeded by the lack of reliable negative training data. Thus, a method to select reliable negative samples becomes vital in the performance improvement. METHODS:Most of the existing computational prediction methods are essentially based on the assumption that similar drugs are inclined to share the same side-effects, which has given rise to remarkable performance. It is also rational to assume an inverse proposition that dissimilar drugs are less likely to share the same side-effects. Based on this inverse similarity hypothesis, we proposed a novel method to select highly-reliable negative samples for side-effect prediction. The first step of our method is to build a drug similarity integration framework to measure the similarity between drugs from different perspectives. This step integrates drug chemical structures, drug target proteins, drug substituents, and drug therapeutic information as features into a unified framework. Then, a similarity score between each candidate negative drug and validated positive drugs is calculated using the similarity integration framework. Those candidate negative drugs with lower similarity scores are preferentially selected as negative samples. Finally, both the validated positive drugs and the selected highly-reliable negative samples are used for predictions. RESULTS:The performance of the proposed method was evaluated on simulative side-effect prediction of 917 DrugBank drugs, comparing with four machine-learning algorithms. Extensive experiments show that the drug similarity integration framework has superior capability in capturing drug features, achieving much better performance than those based on a single type of drug property. Besides, the four machine-learning algorithms achieved significant improvement in macro-averaging F1-score (e.g., SVM from 0.655 to 0.898), macro-averaging precision (e.g., RBF from 0.592 to 0.828) and macro-averaging recall (e.g., KNN from 0.651 to 0.772) complimentarily attributed to the highly-reliable negative samples selected by the proposed method. CONCLUSIONS:The results suggest that the inverse similarity hypothesis and the integration of different drug properties are valuable for side-effect prediction. The selection of highly-reliable negative samples can also make significant contributions to the performance improvement.

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Large-scale prediction and testing of drug activity on side-effect targets.

Publications

Large-scale prediction and testing of drug activity on side-effect targets.

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