Computational methods for predicting the macromolecular targets of drugs and drug-like compounds have evolved as a key technology in drug discovery. However, the established validation protocols leave several key questions regarding the performance and scope of methods unaddressed. For example, prediction success rates are commonly reported as averages over all compounds of a test set and do not consider the structural relationship between the individual test compounds and the training instances. In order to obtain a better understanding of the value of ligand-based methods for target prediction, we benchmarked a similarity-based method and a random forest based machine learning approach (both employing 2D molecular fingerprints) under three testing scenarios: a standard testing scenario with external data, a standard time-split scenario, and a scenario that is designed to most closely resemble real-world conditions. In addition, we deconvoluted the results based on the distances of the individual test molecules from the training data. We found that, surprisingly, the similarity-based approach generally outperformed the machine learning approach in all testing scenarios, even in cases where queries were structurally clearly distinct from the instances in the training (or reference) data, and despite a much higher coverage of the known target space.
Keywords: drug discovery; machine learning; molecular fingerprints; molecular similarity; random forest; target prediction.