IN-SILICO SAFETY PROFILING
Detecting off-target liabilities early in drug discovery is critical to reduce safety-related attrition.
To address this challenge, Prous Institute has developed Symmetry, a predictive analytics platform that enables hypothesis generation and elucidates the therapeutic and safety profiles of small molecules. Symmetry’s Global Mechanism of Action Model (GMoA) identifies the probable molecular targets and mode of action of compounds by screening more than 1,000 relevant mechanisms of action simultaneously in a single predictive model.
In particular, Symmetry GMoA model covers more than 250 target actions essential for secondary pharmacology profiling and provides information on the adverse effects that have been linked to these mechanisms of action.
With its up-to-date, expertly curated training set, Symmetry GMoA effectively predicts on- and off-target activity of small molecules. The model's training set of one million compounds is derived from careful analysis of patents in addition to journals, congresses, public Access databases and data from research collaborations. Symmetry GMoA is therefore able to make predictions based on a comprehensive and novel chemical space.
SYMMETRY GMoA has been applied in order to shed light on potential off-target activities related to safety events encountered during clinical development of a variety of investigational drugs.
An example of this approach corresponds to the novel nicotinic alpha 7 agonist encenicline.
Phase III studies investigating encenicline in Alzheimer’s disease have been placed on clinical hold based on a recommendation from the FDA following the observation of severe gastrointestinal events in some participants. (REFERENCE)
Encenicline has been screened with SYMMETRY GMoA to assess its potential secondary pharmacology profile. number of mechanisms of action with safety alerts related to gastrointestinal disorders are predicted, including 5-HT3 receptor antagonism, 5-HT4 receptor agonism, M3 receptor antagonism, CB1 receptor antagonism and D2 receptor antagonism. Likewise interaction with the following targets associated to gastrointestinal safety events has been predicted: 5-HT2 receptor and 5-HT1 receptor.
The predicted interaction of encenicline with a variety of targets linked to gastrointestinal safety issues could explain safety issues observed in phase III clinical trials. At the same time, it should be taken into consideration that Alzheimer's Disease patients are more likely to suffer gastrointestinal issues and that the patient population in the clinical study may also be treated with AChE inhibitors which have been linked in the past to gastrointestinal safety issues as well.
SYMMETRY GMoA LICENSING INFORMATION
OFF-X subscribers are eligible to a complementary in-silico testing of 10 molecules and special package licensing prices for the SYMMMETRY in-silico predictive analytics platform.
Please Contact us to learn more about how we can help you to optimize your drug R&D activities by minimizing costs and safety-related attrition rates.