Having a clinical drug-induced liver injury (DILI) signal is a surefire way to kill a drug candidate in non-serious indications like pain or chronic indications like diabetes, and will even give oncologists second thoughts as cancer patients are living longer. What can we do to prevent it? A widely accepted strategy for minimizing DILI risk …
Protein-ligand interactions are driven predominantly by strong hydrogen-bonding interactions, de-solvation energetics, and other entropic considerations including ligand lipophilicity. However, the combination of many weaker interactions can contribute to potency, and are often necessary to obtain selectivity when targets and anti-targets have very similar binding pockets. Weak interactions such as Dunitz interactions, polarized C-H hydrogen bonding …
With the biochemistry magic available to the liver, it’s a wonder that anything we consume is well-tolerated. Even carboxylic acids are structural alerts as they can be converted to bioreactive acyl glucoronides. The best we can do as drug hunters is minimize the risk of toxic metabolite formation and apply assays appropriately to select compounds …
There are catalysis geniuses (looking at you, process chemists!) and then there are those of us just looking to put compounds in vials. Here are the simplest conditions that’ll get you what you want 90% of the time. Beyond that you’ll need to ask a guru like Nick White or Malcolm Huestis. Hope this helps. …
When interpreting compound pharmacokinetic (PK) data, it’s helpful to have reference values to compare experimental data to. A compound with a measured rat clearance value of 0.3 L/hr/kg, for example, is being removed at a slow rate relative to rat liver blood flow (3.3 L/hr/kg), indicating that the compound is not rapidly metabolized or excreted …