Accurate prediction of CB2 receptor ligand activity is pivotal for advancing drug discovery targeting this receptor, which is implicated in inflammation, pain management, and neurodegenerative conditions. Although conventional machine learning and deep learning techniques have shown promise, their limited interpretability remains a significant barrier to rational drug design. In this work, we introduce CB2former, a framework that combines a Graph Convolutional Network with a Transformer architecture to predict CB2 receptor ligand activity. By leveraging the Transformer's self attention mechanism alongside the GCN's structural learning capability, CB2former not only enhances predictive performance but also offers insights into the molecular features underlying receptor activity. We benchmark CB2former against diverse baseline models including Random Forest, Support Vector Machine, K Nearest Neighbors, Gradient Boosting, Extreme Gradient Boosting, Multilayer Perceptron, Convolutional Neural Network, and Recurrent Neural Network and demonstrate its superior performance with an R squared of 0.685, an RMSE of 0.675, and an AUC of 0.940. Moreover, attention weight analysis reveals key molecular substructures influencing CB2 receptor activity, underscoring the model's potential as an interpretable AI tool for drug discovery. This ability to pinpoint critical molecular motifs can streamline virtual screening, guide lead optimization, and expedite therapeutic development. Overall, our results showcase the transformative potential of advanced AI approaches exemplified by CB2former in delivering both accurate predictions and actionable molecular insights, thus fostering interdisciplinary collaboration and innovation in drug discovery.

Drug target binding affinity (DTA) is a key criterion for drug screening. Existing experimental methods are time-consuming and rely on limited structural and domain information. While learning-based methods can model sequence and structural information, they struggle to integrate contextual data and often lack comprehensive modeling of drug-target interactions. In this study, we propose a novel DTA prediction method, termed HGTDP-DTA, which utilizes dynamic prompts within a hybrid Graph-Transformer framework. Our method generates context-specific prompts for each drug-target pair, enhancing the model's ability to capture unique interactions. The introduction of prompt tuning further optimizes the prediction process by filtering out irrelevant noise and emphasizing task-relevant information, dynamically adjusting the input features of the molecular graph. The proposed hybrid Graph-Transformer architecture combines structural information from Graph Convolutional Networks (GCNs) with sequence information captured by Transformers, facilitating the interaction between global and local information. Additionally, we adopted the multi-view feature fusion method to project molecular graph views and affinity subgraph views into a common feature space, effectively combining structural and contextual information. Experiments on two widely used public datasets, Davis and KIBA, show that HGTDP-DTA outperforms state-of-the-art DTA prediction methods in both prediction performance and generalization ability.