A Scalable Structure-Aware Multimodal Architecture for Accurate Drug-Target Affinity Prediction.

Abstract

Accurate prediction of drug-target binding affinity (DTA) is a key task in virtual screening. However, current computational methods face a key challenge: sequence-based approaches often fail to capture critical spatial information, while structure-based models rely on computationally expensive 3D coordinates, which restrict their scalability. To address this issue, we propose StructuraDTA, a novel multimodal framework that adopts an implicit structure modeling strategy. Instead of using static protein folding data, our method encodes drug molecular graphs via Graph Isomorphism Networks (GINs) to capture fine-grained topological features. Meanwhile, we optimize protein representations by integrating probabilistic structural priors into a pretrained language model, which effectively simulates thermodynamic conformational flexibility without relying on explicit 3D structural data. A bidirectional cross-attention mechanism is then used to dynamically align these heterogeneous feature modalities. Comprehensive evaluations on the Davis and KIBA benchmark datasets show that StructuraDTA stably outperforms state of-the-art comparison methods. Importantly, the model exhibits strong robustness in cold-start scenarios, and can accurately predict binding affinities for previously unseen drugs and targets. By retaining the predictive performance of structure based models while maintaining the high inference efficiency of sequence-based methods, we provide an accurate and scalable solution to accelerate genome-scale drug discovery research.