approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity.

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed.

Machine Learning Strategies When Transitioning between Biological Assays.

Machine learning is widely used in drug development to predict activity in biological assays based on chemical structure. However, the process of transitioning from one experimental setup to another for the same biological endpoint has not been extensively studied. In a retrospective study, we here explore different modeling strategies of how to combine data from the old and new assays when training conformal prediction models using data from hERG and Na assays.

Predicting the Risk of Phospholipidosis with in Silico Models and an Image-Based in Vitro Screen.

The drug-induced accumulation of phospholipids in lysosomes of various tissues is predominantly observed in regular repeat dose studies, often after prolonged exposure, and further investigated in mechanistic studies prior to candidate nomination. The finding can cause delays in the discovery process inflicting high costs to the affected projects. This article presents an in vitro imaging-based method for early detection of phospholipidosis liability and a hybrid approach for early detection and risk mitigation of phospolipidosis utilizing the in vitro readout with in silico model prediction.

Flagging Drugs That Inhibit the Bile Salt Export Pump.

The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis.

Ligand-based target prediction with signature fingerprints.

When evaluating a potential drug candidate it is desirable to predict target interactions in silico prior to synthesis in order to assess, e.g., secondary pharmacology.