Multi-dimensional search for drug-target interaction prediction by preserving the consistency of attention distribution.

Predicting drug-target interaction (DTI) is a crucial step in the process of drug repurposing and new drug development. Although the attention mechanism has been widely used to capture the interactions between drugs and targets, it mainly uses the Simplified Molecular Input Line Entry System (SMILES) and two-dimensional (2D) molecular graph features of drugs. In this paper, we propose a neural network model called MdDTI for DTI prediction. The model searches for binding sites that may interact with the target from the multiple dimensions of drug structure, namely the 2D substructures and the three-dimensional (3D) spatial structure. For the 2D substructures, we have developed a novel substructure decomposition strategy based on drug molecular graphs and compared its performance with the SMILES-based decomposition method. For the 3D spatial structure of drugs, we constructed spatial feature representation matrices for drugs based on the Cartesian coordinates of heavy atoms (without hydrogen atoms) in each drug. Finally, to ensure the search results of the model are consistent across multiple dimensions, we construct a consistency loss function. We evaluate MdDTI on four drug-target interaction datasets and three independent compound-protein affinity test sets. The results indicate that our model surpasses a series of state-of-the-art models. Case studies demonstrate that our model is capable of capturing the potential binding regions between drugs and targets, and it shows efficacy in drug repurposing. Our code is available at https://github.com/lhhu1999/MdDTI.