Leveraging bounded datapoints to classify molecular potency improvements†

Molecular machine learning algorithms are becoming increasingly powerful at predicting the potency of potential drug candidates to guide molecular discovery, lead series prioritization, and structural optimization. However, a substantial amount of inhibition data is bounded and inaccessible to traditional regression algorithms. Here, we develop a novel molecular pairing approach to process this data. This creates a new classification task of predicting which one of two paired molecules is more potent. This novel classification task can be accurately solved by various, established molecular machine learning algorithms, including XGBoost and Chemprop. Across 230 ChEMBL IC₅₀ datasets, both tree-based and neural network-based “DeltaClassifiers” show improvements over traditional regression approaches in correctly classifying molecular potency improvements. The Chemprop-based deep DeltaClassifier outperformed all here evaluated regression approaches for paired molecules with shared and with distinct scaffolds, highlighting the promise of this approach for molecular optimization and scaffold-hopping.