Thrombotargets (Spain)

Mice are the most commonly used laboratory animal, yet there are limited studies which investigate the effects of repeated handling on their welfare and scientific outcomes. Furthermore, simple methods to evaluate distress in mice are lacking, and specialized behavioral or biochemical tests are often required. Here, two groups of CD1 mice were exposed to either traditional laboratory handling methods or a training protocol with cup lifting for 3 and 5 weeks. The training protocol was designed to habituate the mice to the procedures involved in subcutaneous injection, e.g., removal from the cage, skin pinch. This protocol was followed by two common research procedures: subcutaneous injection and tail vein blood sampling. Two training sessions and the procedures (subcutaneous injection and blood sampling) were video recorded. The mouse facial expressions were then scored, focusing on the ear and eye categories of the mouse grimace scale. Using this assessment method, trained mice expressed less distress than the control mice during subcutaneous injection. Mice trained for subcutaneous injection also had reduced facial scores during blood sampling. We found a clear sex difference as female mice responded to training faster than the male mice, they also had lower facial scores than the male mice when trained. The ear score appeared to be a more sensitive measure of distress than the eye score, which may be more indicative of pain. In conclusion, training is an important refinement method to reduce distress in mice during common laboratory procedures and this can best be assessed using the ear score of the mouse grimace scale.

A method is presented to analyze quantitatively the degree of congenericity of claimed compounds in patent applications. The approach successfully differentiates patents exemplified with highly congeneric compounds of a structurally compact and well defined chemical series from patents containing a more diverse set of compounds around a more vaguely described patent claim. An application to 750 common patents available in SureChEMBL, SureChEMBLccs and ChEMBL is presented and the congenericity of patent compounds in those different sources discussed.

The recent explosion of data linking drugs, proteins, and pathways with safety events has promoted the development of integrative systems approaches to large-scale predictive drug safety. The added value of such approaches is that, beyond the traditional identification of potentially labile chemical fragments for selected toxicity end points, they have the potential to provide mechanistic insights for a much larger and diverse set of safety events in a statistically sound nonsupervised manner, based on the similarity to drug classes, the interaction with secondary targets, and the interference with biological pathways. The combined identification of chemical and biological hazards enhances our ability to assess the safety risk of bioactive small molecules with higher confidence than that using structural alerts only. We are still a very long way from reliably predicting drug safety, but advances toward gaining a better understanding of the mechanisms leading to adverse outcomes represent a step forward in this direction.

The recent availability of a complete interaction matrix between 13 antipsychotic drugs and 34 protein targets (Roth et al. Nat. Rev. Drug Discov. 2004, 3, 353-359) allows to assess the performance of computational methods on their ability to anticipate the entire affinity profile of drugs across multiple targets. The analyses reveal that our current implementations, based on the similarity of drugs against a reference set of small molecules for which pharmacological data is available in the public domain, are able to predict 65 % of the 442 affinities within 1-log unit error, with a level of precision above 92 %. In spite of the relatively small scale of this validation study, the results are indicative that in silico receptorome screening of drugs offers an efficient and cost-effective complement to in vitro screening.