Predicting or Pretending: Artificial Intelligence for Protein-Ligand Interactions Lack of Sufficiently Large and...

Predicting protein-ligand interactions using artificial intelligence (AI) models has attracted great interest in recent years. However, data-driven AI models unequivocally suffer from a lack of sufficiently large and unbiased datasets. Here, we systematically investigated the data biases on the PDBbind and DUD-E datasets. We examined the model performance of atomic convolutional neural network (ACNN) on the PDBbind core set and achieved a Pearson R² of 0.73 between experimental and predicted binding affinities. Strikingly, the ACNN models did not require learning the essential protein-ligand interactions in complex structures and achieved similar performance even on datasets containing only ligand structures or only protein structures, while data splitting based on similarity clustering (protein sequence or ligand scaffold) significantly reduced the model performance. We also identified the property and topology biases in the DUD-E dataset which led to the artificially increased enrichment performance of virtual screening. The property bias in DUD-E was reduced by enforcing the more stringent ligand property matching rules, while the topology bias still exists due to the use of molecular fingerprint similarity as a decoy selection criterion. Therefore, we believe that sufficiently large and unbiased datasets are desirable for training robust AI models to accurately predict protein-ligand interactions.