Do AutoML-Based QSAR Models Fulfill OECD Principles for Regulatory Assessment? A 5-HT1A Receptor Case.

The drug discovery and development process requires a lot of time, financial, and workforce resources. Any reduction in these burdens might benefit all stakeholders in the healthcare domain, including patients, government, and companies. One of the critical stages in drug discovery is a selection of molecular structures with a strong affinity to a particular molecular target. The possible solution is the development of predictive models and their application in the screening process, but due to the complexity of the problem, simple and statistical models might not be sufficient for practical application. The manuscript presents the best-in-class predictive model for the serotonin 1A receptor affinity and its validation according to the Organization for Economic Co-operation and Development guidelines for regulatory purposes. The model was developed based on a database with close to 9500 molecules by using an automatic machine learning tool (AutoML). The model selection was conducted based on the Akaike information criterion value and 10-fold cross-validation routine, and later good predictive ability was confirmed with an additional external validation dataset with over 700 molecules. Moreover, the multi-start technique was applied to test if an automatic model development procedure results in reliable results.

Quantitative Assessment of the Physiological Parameters Influencing QT Interval Response to Medication: Application of Computational Intelligence Tools.

Human heart electrophysiology is complex biological phenomenon, which is indirectly assessed by the measured ECG signal. ECG trace is further analyzed to derive interpretable surrogates including QT interval, QRS complex, PR interval, and T wave morphology. QT interval and its modification are the most commonly used surrogates of the drug triggered arrhythmia, but it is known that the QT interval itself is determined by other nondrug related parameters, physiological and pathological. In the current study, we used the computational intelligence algorithms to analyze correlations between various simulated physiological parameters and QT interval. Terfenadine given concomitantly with 8 enzymatic inhibitors was used as an example. The equation developed with the use of genetic programming technique leads to general reasoning about the changes in the prolonged QT. For small changes of the QT interval, the drug-related IKr and ICa currents inhibition potentials have major impact. The physiological parameters such as body surface area, potassium, sodium, and calcium ions concentrations are negligible. The influence of the physiological variables increases gradually with the more pronounced changes in QT. As the significant QT prolongation is associated with the drugs triggered arrhythmia risk, analysis of the role of physiological parameters influencing ECG seems to be advisable.