Attention-based approach to predict drug-target interactions across seven target superfamilies

Abstract Motivation Drug–target interactions (DTIs) hold a pivotal role in drug repurposing and elucidation of drug mechanisms of action. While single-targeted drugs have demonstrated clinical success, they often exhibit limited efficacy against complex diseases, such as cancers, whose development and treatment is dependent on several biological processes. Therefore, a comprehensive understanding of primary, secondary and even inactive targets becomes essential in the quest for effective and safe treatments for cancer and other indications. The human proteome offers over a thousand druggable targets, yet most FDA-approved drugs bind to only a small fraction of these targets. Results This study introduces an attention-based method (called as MMAtt-DTA) to predict drug–target bioactivities across human proteins within seven superfamilies. We meticulously examined nine different descriptor sets to identify optimal signature descriptors for predicting novel DTIs. Our testing results demonstrated Spearman correlations exceeding 0.72 (P < 0.001) for six out of seven superfamilies. The proposed method outperformed fourteen state-of-the-art machine learning, deep learning and graph-based methods and maintained relatively high performance for most target superfamilies when tested with independent bioactivity data sources. We computationally validated 185 676 drug–target pairs from ChEMBL-V33 that were not available during model training, achieving a reasonable performance with Spearman correlation >0.57 (P < 0.001) for most superfamilies. This underscores the robustness of the proposed method for predicting novel DTIs. Finally, we applied our method to predict missing bioactivities among 3492 approved molecules in ChEMBL-V33, offering a valuable tool for advancing drug mechanism discovery and repurposing existing drugs for new indications. Availability and implementation https://github.com/AronSchulman/MMAtt-DTA.