DTIAM: A unified framework for predicting drug-target interactions, binding affinities and activation/inhibition mechanisms

Abstract

Accurate and robust prediction of drug-target interactions (DTIs) plays a vital role in drug discovery. Despite extensive efforts have been invested in predicting novel DTIs, existing approaches still suffer from insufficient labeled data and cold start problems. More importantly, there is currently a lack of studies focusing on elucidating the mechanism of action (MoA) between drugs and targets. Distinguishing the activation and inhibition mechanisms is critical and challenging in drug development. Here, we introduce a unified framework called DTIAM, which aims to predict interactions, binding affinities, and activation/inhibition mechanisms between drugs and targets. DTIAM learns drug and target representations from large amounts of label-free data through self-supervised pre-training, which accurately extracts the substructure and contextual information of drugs and targets, and thus benefits the downstream prediction based on these representations. DTIAM achieves substantial performance improvement over other state-of-the-art methods in all tasks, particularly in the cold start scenario. Moreover, independent validation demonstrates the strong generalization ability of DTIAM. All these results suggested that DTIAM can provide a practically useful tool for predicting novel DTIs and further distinguishing the MoA of candidate drugs. DTIAM, for the first time, provides a unified framework for accurate and robust prediction of drug-target interactions, binding affinities, and activation/inhibition mechanisms.