Leveraging Image-Derived Phenotypic Measurements for Drug-Target Interaction Predictions.

In recent years, protein kinases have become some of the most significant drug targets in cancer patients. Kinases are known to regulate the activity of many human proteins, and consequently their inhibition has been used to control cancer proliferation. A significant challenge in drug discovery is the rapid and efficient identification of new small molecules. In this study, we propose a novel in silico drug discovery approach to identify kinase targets that impinge on nuclear receptor signaling with data generated using high-content analysis (HCA). A high-throughput imaging dataset was generated from an siRNA human kinome screen on engineered cells that allow direct visualization of effects on estrogen receptor-α or a chimeric progesterone receptor B binding to specific DNA. Two types of kinase descriptors are extracted from these imaging data: first, a population-median-based descriptor and second a bag-of-words (BoW) descriptor that can capture heterogeneity information in the imaging data. Using these descriptors, we provide prediction results of drug-kinase-target interactions based on single-task learning, multi-task learning, and collaborative filtering methods. The best performing model in target-based drug discovery gives an area under the receiver operating characteristic curve (AUC) of 0.86, whereas the best model in ligand-based discovery gives an AUC of 0.79. These promising results suggest that imaging-based information can be used as an additional source of information to existing virtual screening methods, thereby making the drug discovery process more time and cost efficient.