G-K BertDTA: A graph representation learning and semantic embedding-based framework for drug-target affinity prediction

Abstract

Developing new drugs is costly, time-consuming, and risky. Drug-target affinity (DTA), indicating the binding capability between drugs and target proteins, is a crucial indicator for drug development. Accurately predicting interaction strength between new drug-target pairs by analyzing previous experiments aids in screening potential drug molecules, repurposing them, and developing safe and effective medicines. Existing computational models for DTA prediction rely on strings or single-graph neural networks, lacking consideration of protein structure and molecular semantic information, leading to limited accuracy. Our experiments demonstrate that string-based methods may overlook protein conformations, causing a high root mean square error (RMSE) of 3.584 in affinity due to a lack of spatial context. Single graph networks also underperform on topology features, with a 6% lower confidence interval (CI) for activity classification. Absent semantic information also limits generalization across diverse compounds, resulting in 18% increment in RMSE and 5% in misclassifications within quantifications study, restricting potential drug discovery. To address these limitations, we propose G-K BertDTA, a novel framework for accurate DTA prediction incorporating protein features, molecular semantic features, and molecular structural information. In this proposed model, we represent drugs as graphs, with a GIN employed to learn the molecular topological information. For the extraction of protein structural features, we utilize a DenseNet architecture. A knowledge-based BERT semantic model is incorporated to obtain rich pre-trained semantic embeddings, thereby enhancing the feature information. We extensively evaluated our proposed approach on the publicly available benchmark datasets (i.e., KIBA and Davis), and experimental results demonstrate the promising performance of our method, which consistently outperforms previous state-of-the-art approaches. Code is available at https://github.com/AmbitYuki/G-K-BertDTA.