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

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 μM. 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.     

Sur les relations entre la production d'hexosamines et d'hydroxyproline de la part de fibroblastes cultivés in vitro dans différentes concentrations d'O2

Summary Studies and comparison of the hexosamine and hydroxyprolin production by fibroblasts cultivated in vitro at different oxygen concentrations. The results show that the highest hexosamine production occurs at a low oxygen concentration (5%). The highest hydroxyprolin production occurs at 20% O₂; this oxygen concentration is considered as an hyperoxic one for fibroblasts cultivated in vitro. Besides it has been ascertained that the highest sulphated MPS production occurs between 5 and 20% oxygen without any significant variation.