BACKGROUND: Deep learning-based drug-target affinity (DTA) prediction methods have shown impressive performance, despite a high number of training parameters relative to the available data. Previous studies have highlighted the presence of dataset bias by suggesting that models trained solely on protein or ligand structures may perform similarly to those trained on complex structures. However, these studies did not propose solutions and focused solely on analyzing complex structure-based models. Even when ligands are excluded, protein-only models trained on complex structures still incorporate some ligand information at the binding sites. Therefore, it is unclear whether binding affinity can be accurately predicted using only compound or protein features due to potential dataset bias. In this study, we expanded our analysis to comprehensive databases and investigated dataset bias through compound and protein feature-based methods using multilayer perceptron models. We assessed the impact of this bias on current prediction models and proposed the binding affinity similarity explorer (BASE) web service, which provides bias-reduced datasets. RESULTS: By analyzing eight binding affinity databases using multilayer perceptron models, we confirmed a bias where the compound-protein binding affinity can be accurately predicted using compound features alone. This bias arises because most compounds show consistent binding affinities due to high sequence or functional similarity among their target proteins. Our Uniform Manifold Approximation and Projection analysis based on compound fingerprints further revealed that low and high variation compounds do not exhibit significant structural differences. This suggests that the primary factor driving the consistent binding affinities is protein similarity rather than compound structure. We addressed this bias by creating datasets with progressively reduced protein similarity between the training and test sets, observing significant changes in model performance. We developed the BASE web service to allow researchers to download and utilize these datasets. Feature importance analysis revealed that previous models heavily relied on protein features. However, using bias-reduced datasets increased the importance of compound and interaction features, enabling a more balanced extraction of key features. CONCLUSIONS: We propose the BASE web service, providing both the affinity prediction results of existing models and bias-reduced datasets. These resources contribute to the development of generalized and robust predictive models, enhancing the accuracy and reliability of DTA predictions in the drug discovery process. BASE is freely available online at https://synbi2024.kaist.ac.kr/base .