# Benchmarking Single-Pose Docking, Consensus Rescoring, and Supervised ML on the LIT-PCBA Library: A Critical Evaluation of DiffDock, AutoDock-GPU, GNINA, and DiffDock-NMDN

arXiv: https://arxiv.org/abs/2605.01681 · HTML: https://mlsanity.com/paper/2605.01681/

## Key facts

- No citing papers in the map yet (data through 14 Oct 2026).
- Builds on 3 of its 19 references that are in the map.
- First posted on arXiv 3 May 2026.

## Builds on (most cited first, 3 of 3)

- [DiffDock: Diffusion Steps, Twists, and Turns for Molecular Docking](https://mlsanity.com/paper/2210.01776/) (2022)
- [Data Leakage and Redundancy in the LIT-PCBA Benchmark](https://mlsanity.com/paper/2507.21404/) (2025)
- [Deep-Learning Based Docking Methods: Fair Comparisons to Conventional Docking Workflows](https://mlsanity.com/paper/2412.02889/) (2024)

## Abstract (arXiv)

Virtual screening performance depends heavily on the chosen docking and scoring methods. Recent AI-based tools such as DiffDock and NMDN have reported strong benchmark results, but their practical utility on realistic, experimentally-derived datasets remains unclear. Here we perform a large-scale evaluation on the LIT-PCBA library (15 targets, 578,295 ligand-target pairs with experimentally confirmed actives and inactives). We compare AutoDock-GPU and DiffDock for pose generation, followed by rescoring with GNINA and NMDN. We further evaluate rank-based consensus strategies and supervised machine learning models trained on docking features. GNINA rescoring of AutoDock-GPU poses (AutoDock-GNINA) emerged as the strongest single method with a median EF1% of 2.14. DiffDock-based approaches underperformed relative to AutoDock-GNINA, particularly on challenging targets such as OPRK1. Carefully designed consensus ranking improved robustness but did not surpass the best single scorer. Supervised ML re-ranking delivered the largest gains, achieving a median EF1% of 4.49 (+110% over AutoDock-GNINA). Our results highlight that even the best classical+ML hybrid workflows provide only modest early enrichment on realistic benchmarks. We conclude that no single docking method dominates across targets and that rigorously validated, cost-effective combinations with supervised re-ranking currently offer the most practical value for virtual screening.