Towards Precision Protein-Ligand Affinity Prediction Benchmark: A Complete and Modification-Aware DAVIS Dataset

TL;DR

This paper introduces a comprehensive, modification-aware DAVIS dataset for protein-ligand affinity prediction, enabling more realistic benchmarking and improving model robustness to biological modifications in drug discovery.

Contribution

The authors curated a complete, modification-aware DAVIS dataset and proposed new benchmark settings to evaluate model robustness to protein modifications.

Findings

Docking-based models generalize better in zero-shot settings.

Docking-free models overfit to wild-type proteins but improve with fine-tuning.

The dataset enables evaluation of models under biologically realistic conditions.

Abstract

Advancements in AI for science unlocks capabilities for critical drug discovery tasks such as protein-ligand binding affinity prediction. However, current models overfit to existing oversimplified datasets that does not represent naturally occurring and biologically relevant proteins with modifications. In this work, we curate a complete and modification-aware version of the widely used DAVIS dataset by incorporating 4,032 kinase-ligand pairs involving substitutions, insertions, deletions, and phosphorylation events. This enriched dataset enables benchmarking of predictive models under biologically realistic conditions. Based on this new dataset, we propose three benchmark settings-Augmented Dataset Prediction, Wild-Type to Modification Generalization, and Few-Shot Modification Generalization-designed to assess model robustness in the presence of protein modifications. Through extensive evaluation of both docking-free and docking-based methods, we find that docking-based model generalize better in zero-shot settings. In contrast, docking-free models tend to overfit to wild-type proteins and struggle with unseen modifications but show notable improvement when fine-tuned on a small set of modified examples. We anticipate that the curated dataset and benchmarks offer a valuable foundation for developing models that better generalize to protein modifications, ultimately advancing precision medicine in drug discovery. The benchmark is available at: https://github.com/ZhiGroup/DAVIS-complete