Publication Date:
2012-06-23
Description:
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 muM. 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383642/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383642/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lounkine, Eugen -- Keiser, Michael J -- Whitebread, Steven -- Mikhailov, Dmitri -- Hamon, Jacques -- Jenkins, Jeremy L -- Lavan, Paul -- Weber, Eckhard -- Doak, Allison K -- Cote, Serge -- Shoichet, Brian K -- Urban, Laszlo -- AG002132/AG/NIA NIH HHS/ -- GM71896/GM/NIGMS NIH HHS/ -- GM93456/GM/NIGMS NIH HHS/ -- P01 AG002132/AG/NIA NIH HHS/ -- R01 GM071896/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Jun 10;486(7403):361-7. doi: 10.1038/nature11159.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722194" target="_blank"〉PubMed〈/a〉
Keywords:
Blood Platelets/drug effects
;
Chlorotrianisene/adverse effects/chemistry/pharmacology
;
Cyclooxygenase 1/metabolism
;
Cyclooxygenase Inhibitors/adverse effects/pharmacology
;
Databases, Factual
;
Drug Evaluation, Preclinical/*methods
;
*Drug-Related Side Effects and Adverse Reactions
;
Estrogens, Non-Steroidal/adverse effects/pharmacology
;
Forecasting
;
Humans
;
Models, Biological
;
Molecular Targeted Therapy/adverse effects
;
Platelet Aggregation/drug effects
;
Reproducibility of Results
;
Substrate Specificity
;
Toxicity Tests/*methods
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
